title: Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans.
abstract: We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg 85764, Germany.
authors.forename: Brian
authors.initials: B
authors.lastname: Finan
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.forename: Nickki
authors.initials: N
authors.lastname: Ottaway
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Habegger
authors.forename: Kristy M
authors.initials: KM
authors.lastname: Heppner
authors.forename: Henriette
authors.initials: H
authors.lastname: Kirchner
authors.forename: Jenna
authors.initials: J
authors.lastname: Holland
authors.forename: Jazzminn
authors.initials: J
authors.lastname: Hembree
authors.forename: Christine
authors.initials: C
authors.lastname: Raver
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Lockie
authors.forename: David L
authors.initials: DL
authors.lastname: Smiley
authors.forename: Vasily
authors.initials: V
authors.lastname: Gelfanov
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.forename: Susanna
authors.initials: S
authors.lastname: Hofmann
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Jaswant
authors.initials: J
authors.lastname: Gidda
authors.forename: Louis
authors.initials: L
authors.lastname: Vignati
authors.forename: Lianshan
authors.initials: L
authors.lastname: Zhang
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Hauptman
authors.forename: Michele
authors.initials: M
authors.lastname: Lau
authors.forename: Mathieu
authors.initials: M
authors.lastname: Brecheisen
authors.forename: Sabine
authors.initials: S
authors.lastname: Uhles
authors.forename: William
authors.initials: W
authors.lastname: Riboulet
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Hainaut
authors.forename: Elena
authors.initials: E
authors.lastname: Sebokova
authors.forename: Karin
authors.initials: K
authors.lastname: Conde-Knape
authors.forename: Anish
authors.initials: A
authors.lastname: Konkar
authors.forename: Richard D
authors.initials: RD
authors.lastname: DiMarchi
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
mesh_terms: D000215:Acylation / Q000187:drug effects; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D000077270:Exenatide; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000008:administration & dosage / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D000882:Haplorhini / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy; D054795:Incretins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D000069450:Liraglutide; D008297:Male; D051379:Mice; D008875:Middle Aged; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism; D012377:Rodentia / Q000378:metabolism*; D016896:Treatment Outcome; D014688:Venoms / Q000494:pharmacology; D015431:Weight Loss / Q000187:drug effects; D055815:Young Adult
chemical_list: C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D007328:Insulin; D010455:Peptides; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D014688:Venoms; D005749:Gastric Inhibitory Polypeptide; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; C041086:gastric inhibitory polypeptide receptor