Targeting the Incretin/Glucagon System With Triagonists to Treat Diabetes

Abstract

<jats:title>Abstract</jats:title> <jats:p>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 triagonists, 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 isletβ 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.</jats:p>

Glucagon lowers glycemia when β cells are active

“…Yet recently, GCGR agonism has been incorporated into MRAs that seem very promising for lowering both glycemia and body weight. To date, the concept of agonizing the GCGR with MRAs was to harness its effect on energy expenditure while buffering the hyperglycemic response of the liver with increased insulin secretion by GLP-1R or GIPR activity (9). However, recent advances in understanding glucagon action, including the data presented here, support the potential benefit of combining GCGR with GLP-1R agonism at the level of the β cell, where recruitment of both receptors may produce greater insulin secretion.…”

“…Overall, our data support a model in which glucagon serves as an insulinotropic hormone in the fed state and complements rather than opposes insulin action to maintain euglycemia. the pharmacology of glucagon action because numerous efforts are now being made to incorporate GCGR activity into multireceptor agonists (MRAs) to treat diabetic hyperglycemia (9). To date the primary goal of adding glucagon activity to novel MRAs is to promote energy expenditure and reduce food intake, with the caveat that hepatic effects could worsen hyperglycemia.…”

“…To date the primary goal of adding glucagon activity to novel MRAs is to promote energy expenditure and reduce food intake, with the caveat that hepatic effects could worsen hyperglycemia. Combining glucagon activity with GLP-1R (10,11) or GLP-1R/GIPR (12)(13)(14) activity theoretically provides sufficient insulin secretion to buffer the hyperglycemic tendencies of glucagon (9). However, these are mostly theoretical assumptions, and the role of glucagon activity in MRAs has not been carefully parsed.…”

Nonconventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP

“…1). Also tested were GPCR antagonists previously reported to be selective for the GluR (des-His 1 -[Glu 9 ]glucagon, LY2409021, and MK 0893) or the GLP-1R (exendin(9 -39)) or NPY2R (BIIE0246) ( Fig. 1) (29).…”

“…One such agonist for the GLP-1R is exendin-4 (Ex-4) (20,21). Four antagonists of family B GPCRs are exendin-(9 -39) (Ex(9 -39)) acting at an orthosteric site on the GLP-1R (20 -22), des-His 1 -[Glu 9 ]glucagon acting at an orthosteric site on the GluR (23), and LY2409021 (24) and MK 0893 (25) acting at an allosteric site on the GluR (26).…”