Efficacy of glucagon-like peptide-1 and estrogen dual agonist in pancreatic islets protection and pre-clinical models of insulin-deficient diabetes

• Published in: Cell reports. Medicine 2022-04, Vol.3 (4), p.100598, Article 100598
• Main Authors: Fuselier, Taylor, Mota de Sa, Paula, Qadir, M.M. Fahd, Xu, Beibei, Allard, Camille, Meyers, Mathew M., Tiano, Joseph P., Yang, Bin S., Gelfanov, Vasily, Lindsey, Sarah H., Dimarchi, Richard D., Mauvais-Jarvis, Franck
• Format: Article
• Language: English
• Subjects: Animals; diabetes; Diabetes Mellitus - metabolism; dual agonist; estrogen; Estrogen Receptor alpha - metabolism; Estrogens - metabolism; fusion peptides; GLP-1; Glucagon-Like Peptide 1 - pharmacology; Insulin - metabolism; Insulin, Regular, Human - metabolism; islet; Islets of Langerhans - metabolism; Mice; peptides; Proteomics; RPPA; Streptozocin - toxicity; β cell
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2022.100598

We study the efficacy of a glucagon-like peptide-1 (GLP-1) and estrogen dual agonist (GLP1-E2) in pancreatic islet protection. GLP1-E2 provides superior protection from insulin-deficient diabetes induced by multiple low-dose streptozotocin (MLD-STZ-diabetes) and by the Akita mutation in mice than a GLP-1 monoagonist. GLP1-E2 does not protect from MLD-STZ-diabetes in estrogen receptor-α (ERα)-deficient mice and fails to prevent diabetes in Akita mice following GLP-1 receptor (GLP-1R) antagonism, demonstrating the requirement of GLP-1R and ERα for GLP1-E2 antidiabetic actions. In the MIN6 β cell model, GLP1-E2 activates estrogen action following clathrin-dependent, GLP-1R-mediated internalization and lysosomal acidification. In cultured human islet, proteomic bioinformatic analysis reveals that GLP1-E2 amplifies the antiapoptotic pathways activated by monoagonists. However, in cultured mouse islets, GLP1-E2 provides antiapoptotic protection similar to monoagonists. Thus, GLP1-E2 promotes GLP-1 and E2 antiapoptotic signals in cultured islets, but in vivo, additional GLP1-E2 actions in non-islet cells expressing GLP-1R are instrumental to prevent diabetes. [Display omitted] •GLP1-E2 enhances GLP-1-mediated protection of insulin-deficient diabetes in mice•GLP1-E2 activates ERα following GLP-1R internalization and lysosomal acidification•GLP1-E2 amplifies antiapoptotic pathways activated by GLP-1 in human β cells•GLP1-E2 antidiabetic actions involve GLP-1R-expressing cells outside the islets Fuselier et al. report that a glucagon-like peptide-1 and estrogen dual agonist (GLP1-E2) provides superior protection from insulin-deficient diabetes in mice compared to GLP-1 and E2 monoagonists, via targeted delivery to GLP-1 receptor (GLP-1R) and estrogen receptor-α (ERα) in β cells, and non-islet cells co-expressing GLP-1R and ERα.