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: 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 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
• Journal: Science translational medicine (Sci Transl Med) Vol. 5 Issue 209 Pg. 209ra151 (Oct 30 2013) ISSN: 1946-6242 [Electronic] United States
• PMID: 24174327 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• GLP1R protein, human
• Glp1r protein, mouse
• Glp1r protein, rat
• Glucagon-Like Peptide-1 Receptor
• Incretins
• Insulin
• Peptides
• Receptors, Gastrointestinal Hormone
• Receptors, Glucagon
• Venoms
• Gastric Inhibitory Polypeptide
• Liraglutide
• Glucagon-Like Peptide 1
• Exenatide
• gastric inhibitory polypeptide receptor

Topics

• Acylation (drug effects)
• Adolescent
• Adult
• Aged
• Animals
• Diabetes Mellitus, Type 2 (drug therapy)
• Exenatide
• Female
• Gastric Inhibitory Polypeptide (administration & dosage, pharmacology)
• Glucagon-Like Peptide 1 (administration & dosage, analogs & derivatives, pharmacology)
• Glucagon-Like Peptide-1 Receptor
• Glucose Tolerance Test
• Haplorhini (metabolism)
• Humans
• Hyperglycemia (drug therapy)
• Incretins (administration & dosage, pharmacology, therapeutic use)
• Insulin (metabolism)
• Liraglutide
• Male
• Mice
• Middle Aged
• Peptides (pharmacology)
• Rats
• Receptors, Gastrointestinal Hormone
• Receptors, Glucagon (agonists, metabolism)
• Rodentia (metabolism)
• Treatment Outcome
• Venoms (pharmacology)
• Weight Loss (drug effects)
• Young Adult