Date Published: February 22, 2016
Publisher: Public Library of Science
Author(s): Moina Hasni Ebou, Amrit Singh-Estivalet, Jean-Marie Launay, Jacques Callebert, François Tronche, Pascal Ferré, Jean-François Gautier, Ghislaine Guillemain, Bernadette Bréant, Bertrand Blondeau, Jean-Pierre Riveline, Thierry Alquier.
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.
Diabetes mellitus (DM) is one of the most frequent complications of chronic exposure to glucocorticoid (GCs) especially during a Cushing’s syndrome (CS) or after treatment with high doses of GCs. Its prevalence is considered to range from 20 to 50% . In general, the prevalence of glucose metabolism alterations including impaired fasting glycaemia (IFG) and impaired glucose tolerance (IGT) reaches 70% after GCs exposure . More generally, type 2 diabetes (T2D) is associated with a subtle hypercortisolism, suggesting a causal role for GCs in T2D . These abnormalities of glucose metabolism occur as a consequence of insulin resistance and impaired insulin secretion induced by GCs excess . These alterations have been studied in vitro using isolated islets and beta-cell lines. Such studies demonstrated that GCs directly inhibit beta-cell function  and reduce beta cell mass by inducing apoptosis . However, the molecular mechanisms of these effects remain unclear. Therefore, unraveling the mechanisms by which GCs alter glucose homeostasis but more specifically insulin secretion could lead to a better understanding of the beta-cell alterations after GCs excess and more generally in type 2 diabetes.
GCs are key regulators of glucose metabolism. They also play specific roles on beta cells since they induce beta-cell apoptosis, decrease beta-cell mass and inhibit insulin secretion, but the molecular mechanisms are still unclear . We provide here original evidence that relate GCs and serotonin synthesis, a modulator of insulin secretion and beta-cell mass. Our results show that both in vitro and in vivo, GCs exposure inhibits Tph1 and 2 expression resulting in a decrease of serotonin synthesis in islets. We provide further evidence that Tph1 and Tph2 expression is under the control of GCs in beta cells since their expression is increased in islets from GR- mice leading to a dramatic augmentation of serotonin content. Furthermore, beta cells exposed in vitro to GCs display also decreased Tph1 and Tph2 expression with reduced serotonin synthesis and content. Finally, GCs also blocked the stimulation of serotonin synthesis by PRL and the GLP-1 analog exendin-4. These results definitively demonstrate that serotonin synthesis is a major target of GCs in beta cells.