title: Glucocorticoids Inhibit Basal and Hormone-Induced Serotonin Synthesis in Pancreatic Beta Cells.
abstract: Diabetes is a major complication of chronic Glucocorticoids (GCs) treatment. GCs induce insulin resistance and also inhibit insulin secretion from pancreatic beta cells. Yet, a full understanding of this negative regulation remains to be deciphered. In the present study, we investigated whether GCs could inhibit serotonin synthesis in beta cell since this neurotransmitter has been shown to be involved in the regulation of insulin secretion. To this aim, serotonin synthesis was evaluated in vitro after treatment with GCs of either islets from CD1 mice or MIN6 cells, a beta-cell line. We also explored the effect of GCs on the stimulation of serotonin synthesis by several hormones such as prolactin and GLP 1. We finally studied this regulation in islet in two in vivo models: mice treated with GCs and with liraglutide, a GLP1 analog, and mice deleted for the glucocorticoid receptor in the pancreas. We showed in isolated islets and MIN6 cells that GCs decreased expression and activity of the two key enzymes of serotonin synthesis, Tryptophan Hydroxylase 1 (Tph1) and 2 (Tph2), leading to reduced serotonin contents. GCs also blocked the induction of serotonin synthesis by prolactin or by a previously unknown serotonin activator, the GLP-1 analog exendin-4. In vivo, activation of the Glucagon-like-Peptide-1 receptor with liraglutide during 4 weeks increased islet serotonin contents and GCs treatment prevented this increase. Finally, islets from mice deleted for the GR in the pancreas displayed an increased expression of Tph1 and Tph2 and a strong increased serotonin content per islet. In conclusion, our results demonstrate an original inhibition of serotonin synthesis by GCs, both in basal condition and after stimulation by prolactin or activators of the GLP-1 receptor. This regulation may contribute to the deleterious effects of GCs on beta cells.
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Sorbonne Universités, UPMC, Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.
authors.forename: Moina
authors.initials: M
authors.lastname: Hasni Ebou
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Sorbonne Universités, UPMC, Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.
authors.forename: Amrit
authors.initials: A
authors.lastname: Singh-Estivalet
authors.affiliation: INSERM U942, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Lariboisière, Service de Biochimie, Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.affiliation: INSERM U942, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Lariboisière, Service de Biochimie, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Callebert
authors.affiliation: Sorbonne Universités, UPMC, Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|CNRS UMR INSERM 952-CNRS 7224, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Tronche
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Sorbonne Universités, UPMC, Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Ferré
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Sorbonne Universités, UPMC, Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Department of Diabetes and Endocrinology, Hôpital Lariboisière, AP-HP, Paris, France.|Université Paris Diderot, Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gautier
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Sorbonne Universités, UPMC, Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Guillemain
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Sorbonne Universités, UPMC, Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Bréant
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Sorbonne Universités, UPMC, Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Blondeau
authors.affiliation: INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Sorbonne Universités, UPMC, Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.|Department of Diabetes and Endocrinology, Hôpital Lariboisière, AP-HP, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Riveline
mesh_terms: D000818:Animals; D002460:Cell Line; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives; D005938:Glucocorticoids / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D011388:Prolactin / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology
chemical_list: D005938:Glucocorticoids; D010455:Peptides; D014688:Venoms; D012701:Serotonin; D052216:Glucagon-Like Peptide 1; D011388:Prolactin; D000077270:Exenatide; D014365:Tryptophan Hydroxylase