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Capozzi, M.E.* ; DiMarchi, R.D.* ; Tschöp, M.H. ; Finan, B.* ; Campbell, J.E.*

Targeting the incretin/glucagon system with triagonists to treat diabetes.

Endocr. Rev. 39, 719-738 (2018)
Verlagsversion DOI PMC
Free by publisher
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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 sequenceintermixed 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 islet beta 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Review
Korrespondenzautor
Schlagwörter Dependent Insulinotropic Polypeptide; Glucagon-like Peptide-1; Gastric-inhibitory Polypeptide; Vertical Sleeve Gastrectomy; Dipeptidyl Peptidase-4 Inhibitors; Adipose-tissue Metabolism; Receptor Knockout Mice; Once-daily Liraglutide; Triple-acting Agonist; Reduces Plaque Load
ISSN (print) / ISBN 0163-769X
e-ISSN 1945-7189
Zeitschrift Endocrine Reviews
Quellenangaben Band: 39, Heft: 5, Seiten: 719-738 Artikelnummer: , Supplement: ,
Verlag The Endocrine Society
Verlagsort Bethesda, Md.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)