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El, K.* ; Douros, J.D.* ; Willard, F.S.* ; Novikoff, A. ; Sargsyan, A.* ; Perez-Tilve, D.* ; Wainscott, D.B.* ; Yang, B.* ; Chen, A.* ; Wothe, D.* ; Coupland, C. ; Tschöp, M.H. ; Finan, B.* ; D'Alessio, D.A.* ; Sloop, K.W.* ; Müller, T.D. ; Campbell, J.E.*

The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets.

Nat. Metab. 5, 945-954 (2023)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) mediate insulin responses that are proportionate to nutrient intake to facilitate glucose tolerance1. The GLP-1 receptor (GLP-1R) is an established drug target for the treatment of diabetes and obesity2, whereas the therapeutic potential of the GIP receptor (GIPR) is a subject of debate. Tirzepatide is an agonist at both the GIPR and GLP-1R and is a highly effective treatment for type 2 diabetes and obesity3,4. However, although tirzepatide activates GIPR in cell lines and mouse models, it is not clear whether or how dual agonism contributes to its therapeutic benefit. Islet beta cells express both the GLP-1R and the GIPR, and insulin secretion is an established mechanism by which incretin agonists improve glycemic control5. Here, we show that in mouse islets, tirzepatide stimulates insulin secretion predominantly through the GLP-1R, owing to reduced potency at the mouse GIPR. However, in human islets, antagonizing GIPR activity consistently decreases the insulin response to tirzepatide. Moreover, tirzepatide enhances glucagon secretion and somatostatin secretion in human islets. These data demonstrate that tirzepatide stimulates islet hormone secretion from human islets through both incretin receptors.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Dependent Insulinotropic Polypeptide; Glucagon-like Peptide-1; Blood-glucose Improves; Glp-1 Receptor Agonist; Competitive Antagonist; Glycemic Control; Weight-loss; Normalization; Gip(3-30)nh2; Somatostatin
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Zeitschrift Nature metabolism
Quellenangaben Band: 5, Heft: 6, Seiten: 945-954 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
Förderungen Proteostasis
Novo Nordisk
Eli Lilly
Helmsley Charitable Trust Foundation
ERC-CoG
German Center for Diabetes Research (DZD e.V.)
German Research Foundation
European Research Council (ERC)-AdG HypoFlam grant
NIH NIDDK