Journal article
Weiwei Xu, F. Ashford, S. Bitsi, L. Schiffer, Fahd Qadir, W. Arlt, Alejandra Tomas, D. Hodson, F. Mauvais-Jarvis
bioRxiv, 2020
bioRxiv, 2020
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APA
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Xu, W., Ashford, F., Bitsi, S., Schiffer, L., Qadir, F., Arlt, W., … Mauvais-Jarvis, F. (2020). Testosterone enhances GLP-1 efficacy at the plasma membrane and endosomes to augment insulin secretion in male pancreatic β cells. BioRxiv.
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Xu, Weiwei, F. Ashford, S. Bitsi, L. Schiffer, Fahd Qadir, W. Arlt, Alejandra Tomas, D. Hodson, and F. Mauvais-Jarvis. “Testosterone Enhances GLP-1 Efficacy at the Plasma Membrane and Endosomes to Augment Insulin Secretion in Male Pancreatic β Cells.” bioRxiv (2020).
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Xu, Weiwei, et al. “Testosterone Enhances GLP-1 Efficacy at the Plasma Membrane and Endosomes to Augment Insulin Secretion in Male Pancreatic β Cells.” BioRxiv, 2020.
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@article{weiwei2020a,
title = {Testosterone enhances GLP-1 efficacy at the plasma membrane and endosomes to augment insulin secretion in male pancreatic β cells},
year = {2020},
journal = {bioRxiv},
author = {Xu, Weiwei and Ashford, F. and Bitsi, S. and Schiffer, L. and Qadir, Fahd and Arlt, W. and Tomas, Alejandra and Hodson, D. and Mauvais-Jarvis, F.}
}
Abstract
Male mice with elimination of the androgen receptor (AR) in islet β cells (βARKO) exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hypoinsulinemia and hyperglycemia when challenged with a Western diet. Testosterone activation of an extranuclear AR in β cells potentiates GSIS by amplifying the insulinotropic action of glucagon-like peptide-1 (GLP-1). Here, using a combination of βARKO and β cell-selective GLP-1 receptor knockout mice and their islets, we show that AR activation in β cells amplifies the insulinotropic effect of islet-derived GLP-1. In β cell models expressing cAMP sensors, testosterone enhances the ability of GLP-1, but not that of glucose-dependent insulinotropic polypeptide or glucagon, to produce cAMP. Accordingly, testosterone selectively enhances the ability of GLP-1 to potentiate GSIS. Notably, testosterone enhances GLP-1 production of cAMP at the plasma membrane and endosomes. In male mouse and human islets, the insulinotropic effect of testosterone is abolished following inhibition of the membrane and endosomal cAMP-dependent protein kinase A and exchange protein activated by cAMP islet 2 pathways. Thus, membrane localization of AR enhances the ability of the GLP-1 receptor to produce cAMP, thus increasing glucose-stimulated insulin exocytosis. Significance Statement This study reveals that testosterone, acting on the androgen receptor (AR) in insulin-producing β cells amplifies the insulinotropic action of glucagon-like peptide-1 (GLP-1) by increasing GLP-1-mediated production of cAMP at the plasma membrane and endosomal compartments, to promote insulin vesicles exocytosis in human β cells. This study establishes a novel biological paradigm in which membrane location of a steroid nuclear receptor enhances the ability of a G protein-coupled receptor to produce cAMP. It has exceptional clinical significance for targeted delivery of testosterone to β cells in the large population of aging and androgen-deficient men who are at increased risk of diabetes.
