Skip to main content

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

Publication ,  Journal Article
El, K; Douros, JD; Willard, FS; Novikoff, A; Sargsyan, A; Perez-Tilve, D; Wainscott, DB; Yang, B; Chen, A; Wothe, D; Coupland, C; Tschöp, MH ...
Published in: Nat Metab
June 2023

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Nat Metab

DOI

EISSN

2522-5812

Publication Date

June 2023

Volume

5

Issue

6

Start / End Page

945 / 954

Location

Germany

Related Subject Headings

  • Mice
  • Islets of Langerhans
  • Insulin
  • Incretins
  • Hypoglycemic Agents
  • Humans
  • Glucagon-Like Peptide Receptors
  • Gastric Inhibitory Polypeptide
  • Cells, Cultured
  • Animals
 

Citation

APA
Chicago
ICMJE
MLA
NLM
El, K., Douros, J. D., Willard, F. S., Novikoff, A., Sargsyan, A., Perez-Tilve, D., … Campbell, J. E. (2023). The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets. Nat Metab, 5(6), 945–954. https://doi.org/10.1038/s42255-023-00811-0
El, Kimberley, Jonathan D. Douros, Francis S. Willard, Aaron Novikoff, Ashot Sargsyan, Diego Perez-Tilve, David B. Wainscott, et al. “The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets.Nat Metab 5, no. 6 (June 2023): 945–54. https://doi.org/10.1038/s42255-023-00811-0.
El K, Douros JD, Willard FS, Novikoff A, Sargsyan A, Perez-Tilve D, et al. The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets. Nat Metab. 2023 Jun;5(6):945–54.
El, Kimberley, et al. “The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets.Nat Metab, vol. 5, no. 6, June 2023, pp. 945–54. Pubmed, doi:10.1038/s42255-023-00811-0.
El K, Douros JD, Willard FS, Novikoff A, Sargsyan A, Perez-Tilve D, Wainscott DB, Yang B, Chen A, Wothe D, Coupland C, Tschöp MH, Finan B, D’Alessio DA, Sloop KW, Müller TD, Campbell JE. The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets. Nat Metab. 2023 Jun;5(6):945–954.

Published In

Nat Metab

DOI

EISSN

2522-5812

Publication Date

June 2023

Volume

5

Issue

6

Start / End Page

945 / 954

Location

Germany

Related Subject Headings

  • Mice
  • Islets of Langerhans
  • Insulin
  • Incretins
  • Hypoglycemic Agents
  • Humans
  • Glucagon-Like Peptide Receptors
  • Gastric Inhibitory Polypeptide
  • Cells, Cultured
  • Animals