2. Academic Validation
  3. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans

Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans

  • Sci Transl Med. 2013 Oct 30;5(209):209ra151. doi: 10.1126/scitranslmed.3007218.
Brian Finan 1,  Tao Ma,  Nickki Ottaway,  Timo D Müller,  Kirk M Habegger,  Kristy M Heppner,  Henriette Kirchner,  Jenna Holland,  Jazzminn Hembree,  Christine Raver,  Sarah H Lockie,  David L Smiley,  Vasily Gelfanov,  Bin Yang,  Susanna Hofmann,  Dennis Bruemmer,  Daniel J Drucker,  Paul T Pfluger,  Diego Perez-Tilve,  Jaswant Gidda,  Louis Vignati,  Lianshan Zhang,  Jonathan B Hauptman,  Michele Lau,  Mathieu Brecheisen,  Sabine Uhles,  William Riboulet,  Emmanuelle Hainaut,  Elena Sebokova,  Karin Conde-Knape,  Anish Konkar,  Richard D DiMarchi,  Matthias H Tschöp
Affiliations

Affiliation

  • 1 Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg 85764, Germany.
PMID: 24174327 DOI: 10.1126/scitranslmed.3007218
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.

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