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GLP‑1 metabolite GLP‑1(9–36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion – 21/12/2023

Gandasi graphical abstract

Nikhil R. Gandasi, Rui Gao, Lakshmi Kothegala, Abigail Pearce, Cristiano Santos, Samuel Acreman, Davide Basco, Anna Benrick, Margarita V. Chibalina, Anne Clark, Claudia Guida, Matthew Harris, Paul R. V. Johnson, Jakob G. Knudsen, Jinfang Ma, Caroline Miranda, Makoto Shigeto, Andrei I. Tarasov, Ho Yan Yeung, Bernard Thorens, Ingrid W. Asterholm, Quan Zhang, Reshma Ramracheya, Graham Ladds, Patrik Rorsman

The incretin hormone glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and inhibits glucagon secretion, with both effects contributing to its blood glucose-lowering effect. GLP-1 is secreted in the gut as GLP-1(7–36), which is rapidly degraded to GLP-1(9–36) and which was previously believed to be biologically inactive. In this issue, Gandasi et al (https://doi.org/10.1007/s00125-023-06060-w) show that GLP-1(9–36), while lacking insulin releasing capacity, strongly and potently inhibits glucagon secretion. They demonstrate that circulating GLP-1(9–36) functions as a systemic inhibitor of glucagon secretion and that this effect is impaired in type 2 diabetes. The capacity of GLP-1(9–36) to inhibit glucagon secretion is prevented by glucagon receptor antagonists and the marked increase in circulating glucagon after administration of such compounds may (in part) be mediated by the removal of the glucagonostatic effects of GLP-1(9–36). The authors suggest that GLP-1(9–36) is more than just a biologically inactive metabolite and that it has many properties that qualify it as a new systemic glucagonostatic hormone.

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