Glucagonlike peptide 1 (GLP-1) receptor agonists have been effective in treating type 2 diabetes but may be enhanced by new intermixed peptides.
reduce weight and lower blood sugar levels in type 2 diabetes patients.
The efficacy of GLP-1 receptor-directed treatments is limited compared to bariatric surgery.
New intermixed peptides combining GLP-1, glucagon, and glucose-dependent insulinotropic peptide (GIP) could target multiple receptors.
Multireceptor agonists may improve the biological activity of GLP-1 by expanding the range of tissue targets.
Preclinical and clinical findings suggest that these dual and could provide a novel approach to treating metabolic dysfunction.
Simplified
Glucagonlike peptide 1 (GLP-1) receptor agonists have been efficacious for the treatment of type 2 diabetes due to their ability to reduce weight and attenuate hyperglycemia. However, the activity of glucagonlike peptide 1 receptor-directed strategies is submaximal, and the only potent, sustainable treatment of metabolic dysfunction is bariatric surgery, necessitating the development of unique therapeutics. GLP-1 is structurally related to glucagon and glucose-dependent insulinotropic peptide (GIP), allowing for the development of intermixed, unimolecular peptides with activity at each of their respective receptors. In this review, we discuss the range of tissue targets and added benefits afforded by the inclusion of each of GIP and glucagon. We discuss considerations for the development of sequence-intermixed dual agonists and , highlighting the importance of evaluating balanced signaling at the targeted receptors. Several multireceptor agonist peptides have been developed and evaluated, and the key preclinical and clinical findings are reviewed in detail. The biological activity of these multireceptor agonists are founded in the success of GLP-1-directed strategies; by including GIP and glucagon components, these multireceptor agonists are thought to enhance GLP-1's activities by broadening the tissue targets and synergizing at tissues that express multiple receptors, such at the brain and pancreatic islet β cells. The development and utility of balanced, unimolecular multireceptor agonists provide both a useful tool for querying the actions of incretins and glucagon during metabolic disease and a unique drug class to treat type 2 diabetes with unprecedented efficacy.
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