Science translational medicineNov 1, 2013

Single molecules activating two incretin hormones improve metabolism in rodents, monkeys, and humans

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 6, 2026

Abstract

A peptide co-agonist showed enhanced efficacy in lowering blood sugar and reducing fat mass compared to selective GLP-1 agonists.

The dual incretin co-agonist was effective in rodent models of obesity and diabetes, including db/db mice and ZDF rats.
It demonstrated superior antihyperglycemic effects and insulin secretion enhancement compared to selective GLP-1 agonists.
In addition, it showed synergistic effects in decreasing fat mass in obese rodents, while selective GIP agonists had minimal impact.
The co-agonist addressed two key factors of diabesity: insulin resistance caused by excess fat and insufficient insulin production.
Pharmacokinetic modifications, such as lipidation or PEGylation, improved the duration of action, allowing for less frequent dosing.
The dual incretin agonist minimized gastrointestinal side effects commonly associated with selective GLP-1-based treatments.

Simplified

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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Single molecules activating two incretin hormones improve metabolism in rodents, monkeys, and humans

Abstract

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