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

Taylor Fuselier; Paula Mota de Sa; M M Fahd Qadir; Beibei Xu; Camille Allard; Mathew M Meyers; Joseph P Tiano; Bin S Yang; Vasily Gelfanov; Sarah H Lindsey; Richard D Dimarchi; Franck Mauvais-Jarvis

doi:10.1016/j.xcrm.2022.100598

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

Cell Rep Med. 2022 Apr 7;3(4):100598. doi: 10.1016/j.xcrm.2022.100598. eCollection 2022 Apr 19.

Authors

Affiliations

¹ Deming Department of Medicine, Section of Endocrinology and Metabolism, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
² Deming Department of Medicine, Section of Endocrinology and Metabolism, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA; Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Healthcare System Medical Center, New Orleans, LA 70119, USA.
³ Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
⁴ Novo Nordisk Research Center Indianapolis, Indianapolis, IN 46241, USA.
⁵ Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA 70112, USA; Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
⁶ Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
⁷ Deming Department of Medicine, Section of Endocrinology and Metabolism, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA; Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Healthcare System Medical Center, New Orleans, LA 70119, USA. Electronic address: [email protected].

Abstract

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.

Keywords: GLP-1; RPPA; diabetes; dual agonist; estrogen; fusion peptides; islet; peptides; proteomics; β cell.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus* / metabolism
Estrogen Receptor alpha / metabolism
Estrogens / metabolism
Glucagon-Like Peptide 1 / pharmacology
Insulin / metabolism
Insulin, Regular, Human / metabolism
Islets of Langerhans* / metabolism
Mice
Proteomics
Streptozocin / toxicity

Substances

Estrogen Receptor alpha
Estrogens
Insulin
Insulin, Regular, Human
Streptozocin
Glucagon-Like Peptide 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding