ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2022) 19 10.17 | DOI: 10.1530/ey.19.10.17

ESPEYB19 10. Type 1 Diabetes New treatments (1 abstracts)

10.17. Efficacy of glucagon-like peptide-1 and estrogen dual agonist in pancreatic islets protection and preclinical models of insulin-deficient diabetes

Fuselier T , Mota de Sa P , Qadir MMF , Xu B , Allard C , Meyers MM , Tiano JP , Yang BS , Gelfanov V , Lindsey SH , Dimarchi RD & Mauvais-Jarvis F



Cell Rep Med 2022;3:100598. https://pubmed.ncbi.nlm.nih.gov/35492248/

Brief Summary: This study used a combination of mice models and cultured human islets to show that a glucagon-like peptide-1 (GLP-1) and estrogen (E2) dual agonist (GLP1-E2) provides superior protection from insulin-deficient diabetes compared to GLP-1 and E2 monoagonists.

Pancreatic islet protection is a major therapeutic goal in diabetes research. Estrogens are known to have antidiabetic properties, and previous studies showed their ability to promote beta cell survival and function both in animal models and cultured human islets (1). However, the use of estrogens as a potential diabetes preventive therapy is limited by their adverse reproductive effects. The dual agonist GLP-1-E2, used in this study, represents a potential way to selectively direct estrogens to pancreatic beta cells, which express both GLP-1 (GLP-1R) and estrogen receptors (ER-α) (2). Through a series of elegant studies, clear evidence emerged that the GLP1-E2 enhances GLP-1-mediated protection of insulin deficient diabetes in mice and that it requires the presence of both GLP-1R and estrogen receptors to exert its functions.

The dual agonist GLP1-E2 activates ER-α following GLP-1R internalization and lysosomal acidification. GLP1-E2 amplifies antiapoptotic pathways activated by GLP-1 in human beta cells. The findings also suggest that the GLP1-E2 antidiabetic actions involve GLP-1R-expressing cells outside the beta cells. Of note, GLP1-E2 did not have any feminizing effects in treated male mice, nor any effect on blood pressure or heart rate.

This study opens new avenues for research to optimize GLP1–E2 agonists, which in future could be a therapeutic option to protect functional β-cell mass in early stages of T1D.

References: 1. Mauvais-Jarvis F, Clegg DJ, Hevener AL. The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev 2013;34:309-38. 2. Tiano JP, Tate CR, Yang BS, DiMarchi R, Mauvais-Jarvis F. Effect of targeted estrogen delivery using glucagon-like peptide-1 on insulin secretion, insulin sensitivity and glucose homeostasis. Sci Rep 2015;5:10211.

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