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

Brian Finan, 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 GiddaLouis 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

*Korrespondierende/r Autor/-in für diese Arbeit
166 Zitate (Scopus)

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.

OriginalspracheEnglisch
Aufsatznummer209ra151
ZeitschriftScience Translational Medicine
Jahrgang5
Ausgabenummer209
ISSN1946-6234
DOIs
PublikationsstatusVeröffentlicht - 30.10.2013

Strategische Forschungsbereiche und Zentren

  • Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)

DFG-Fachsystematik

  • 205-17 Endokrinologie, Diabetologie, Metabolismus

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