Targeting the Incretin/Glucagon System with Triagonists to Treat Diabetes.

Targeting the Incretin/Glucagon System with Triagonists to Treat Diabetes. Endocr Rev. 2018 Jun 13;: Authors: Capozzi ME, DiMarchi RD, Tschöp MH, Finan B, Campbell JE Abstract Glucagon-like 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 GLP-1R-directed strategies is sub-maximal, and the only potent, sustainable treatment for metabolic dysfunction is bariatric surgery, necessitating the development of novel 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- and tri-agonists, highlighting the importance of evaluating balanced signaling at the targeted receptors. Several multi-receptor agonist peptides have been developed and evaluated, and the key pre-clinical and clinical findings are reviewed in detail. The biological activity of these multi-receptor agonists are founded in the success of GLP-1-directed strategies; by including GIP and glucagon components these multi-receptor agonists are thought to enhance GLP-1's activit...
Source: Endocrine Reviews - Category: Endocrinology Tags: Endocr Rev Source Type: research