Details

Autor(en) / Beteiligte

• Finan, Brian
• Ma, Tao
• Ottaway, Nickki
• Müller, Timo D
• Habegger, Kirk M
• Heppner, Kristy M
• Kirchner, Henriette
• Holland, Jenna
• Hembree, Jazzminn
• Raver, Christine
• Lockie, Sarah H
• Smiley, David L
• Gelfanov, Vasily
• Yang, Bin
• Hofmann, Susanna
• Bruemmer, Dennis
• Drucker, Daniel J
• Pfluger, Paul T
• Perez-Tilve, Diego
• Gidda, Jaswant
• Vignati, Louis
• Zhang, Lianshan
• Hauptman, Jonathan B
• Lau, Michele
• Brecheisen, Mathieu
• Uhles, Sabine
• Riboulet, William
• Hainaut, Emmanuelle
• Sebokova, Elena
• Conde-Knape, Karin
• Konkar, Anish
• DiMarchi, Richard D
• Tschöp, Matthias H

Titel

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

Ist Teil von

• Science translational medicine, 2013-10, Vol.5 (209), p.209ra151

Ort / Verlag

United States

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.