Efficacy of glucagon-like peptide-1 and estrogen dual agonist in pancreatic islets protection and pre-clinical models of insulin-deficient diabetes
Cell Reports Medicine. 2022-04-01; 3(4): 100598
DOI: 10.1016/j.xcrm.2022.100598
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Fuselier T(1), Mota de Sa P(1)(2)(3), Qadir MMF(1)(2)(3), Xu B(1), Allard C(1),
Meyers MM(4), Tiano JP(4), Yang BS(5), Gelfanov V(5), Lindsey SH(2)(6), Dimarchi
RD(7), Mauvais-Jarvis F(1)(2)(3).
Author information:
(1)Deming Department of Medicine, Section of Endocrinology and Metabolism, Tulane
University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
(2)Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA
70112, USA.
(3)Southeast Louisiana Veterans Healthcare System Medical Center, New Orleans, LA
70119, USA.
(4)Department of Medicine, Feinberg School of Medicine, Northwestern University,
Chicago, IL 60611, USA.
(5)Novo Nordisk Research Center Indianapolis, Indianapolis, IN 46241, USA.
(6)Department of Pharmacology, Tulane University School of Medicine, New Orleans,
LA 70112, USA.
(7)Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
Comment in
Nat Rev Endocrinol. 2022 Jun;18(6):331.
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.
© 2022 The Author(s).
Conflict of interest statement: F.M.J. received consulting fees from Mithra
Pharmaceutical, Inc. R.D. received research funding and is a cofounder of
Marcadia biotech. R.D. has a conflict that pertains to IP at Indiana University
and its license to Marcadia Biotech with Patents #9,127,088 and #9,783,592
related to this work. Other authors declare no competing financial interest.