Hasni Ebou Moina, Singh-Estivalet Amrit, Launay Jean-Marie, Callebert Jacques, Tronche François, Ferré Pascal, Gautier Jean-François, Guillemain Ghislaine, Bréant Bernadette, Blondeau Bertrand, Riveline Jean-Pierre
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.
PLoS One. 2016 Feb 22;11(2):e0149343. doi: 10.1371/journal.pone.0149343. eCollection 2016.
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.
糖尿病是慢性糖皮质激素（GCs）治疗的主要并发症。GCs会诱导胰岛素抵抗，还会抑制胰腺β细胞分泌胰岛素。然而，对这种负调控的全面理解仍有待阐明。在本研究中，我们研究了GCs是否会抑制β细胞中血清素的合成，因为这种神经递质已被证明参与胰岛素分泌的调节。为此，在用CD1小鼠的胰岛或β细胞系MIN6细胞进行GCs处理后，在体外评估血清素的合成。我们还探讨了GCs对几种激素（如催乳素和GLP - 1）刺激血清素合成的影响。我们最终在两种体内模型的胰岛中研究了这种调节：用GCs和GLP - 1类似物利拉鲁肽处理的小鼠，以及胰腺中糖皮质激素受体缺失的小鼠。我们在分离的胰岛和MIN6细胞中发现，GCs降低了血清素合成的两种关键酶色氨酸羟化酶1（Tph1）和2（Tph2）的表达和活性，导致血清素含量降低。GCs还阻断了催乳素或一种先前未知的血清素激活剂GLP - 1类似物艾塞那肽 - 4对血清素合成的诱导。在体内，用利拉鲁肽激活胰高血糖素样肽 - 1受体4周可增加胰岛血清素含量，而GCs治疗可阻止这种增加。最后，胰腺中GR缺失的小鼠的胰岛显示Tph1和Tph2的表达增加，每个胰岛的血清素含量大幅增加。总之，我们的结果表明，GCs在基础状态以及在催乳素或GLP - 1受体激活剂刺激后，对血清素合成具有原始的抑制作用。这种调节可能导致GCs对β细胞产生有害影响。
