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.

Glycyrrhizae Radix et Rhizoma is regarded as one of the most popular and commonly used herbal medicines and has been used in traditional Chinese medicine (TCM) prescriptions for over 2000 years. Pentacyclic triterpene saponins are common secondary metabolites in these plants, which are synthesized via the isoprenoid pathway to produce a hydrophobic triterpenoid aglycone containing a hydrophilic sugar chain. This paper systematically summarizes the chemical structures of triterpene saponins in Glycyrrhizae Radix et Rhizoma and reviews and updates their main biological activities studies. Furthermore, the solubilization characteristics, influences, and mechanisms of Glycyrrhizae Radix et Rhizoma are elaborated. Solubilization of the triterpene saponins from Glycyrrhizae Radix et Rhizoma occurs because they contain the nonpolar sapogenin and water-soluble sidechain. The possible factors affecting the solubilization of Glycyrrhizae Radix et Rhizoma are mainly other crude drugs and the pH of the decoction. Triterpene saponins represented by glycyrrhizin from Glycyrrhizae Radix et Rhizoma characteristically form micelles due to amphiphilicity, which makes solubilization possible. This overview provides guidance regarding a better understanding of GlycyrrhizaeRadix et Rhizoma and its TCM compatibility, alongside a theoretical basis for the further development and utilization of Glycyrrhizae Radix et Rhizoma.