Authors: Bähr I; Mühlbauer E; Albrecht E; Peschke E
Abstract: Melatonin has been shown to modulate glucose metabolism by influencing insulin secretion. Recent investigations have also indicated a regulatory function of melatonin on the pancreatic alpha-cells. The present in vitro and in vivo studies evaluated whether melatonin mediates its effects via melatonin receptors and which signaling cascade is involved. Incubation experiments using the glucagon-producing mouse pancreatic alpha-cell line alphaTC1 clone 9 (alphaTC1.9) as well as isolated pancreatic islets of rats and mice revealed that melatonin increases glucagon secretion. Preincubation of alphaTC1.9 cells with the melatonin receptor antagonists luzindole and 4P-PDOT abolished the glucagon-stimulatory effect of melatonin. In addition, glucagon secretion was lower in the pancreatic islets of melatonin receptor knockout mice than in the islets of the wild-type (WT) control animals. Investigations of melatonin receptor knockout mice revealed decreased plasma glucagon concentrations and elevated mRNA expression levels of the hepatic glucagon receptor when compared to WT mice. Furthermore, studies using pertussis toxin, as well as measurements of cAMP concentrations, ruled out the involvement of Galphai- and Galphas-coupled signaling cascades in mediating the glucagon increase induced by melatonin. In contrast, inhibition of phospholipase C in alphaTC1.9 cells prevented the melatonin-induced effect, indicating the physiological relevance of the Galphaq-coupled pathway. Our data point to the involvement of the phosphatidylinositol 3-kinase signaling cascade in mediating melatonin effects in pancreatic alpha-cells. In conclusion, these findings provide evidence that the glucagon-stimulatory effect of melatonin in pancreatic alpha-cells is melatonin receptor mediated, thus supporting the concept of melatonin-modulated and diurnal glucagon release.
Keywords: Animals; Cell Line; Cyclic AMP/metabolism; Diabetes Mellitus, Type 2/enzymology; Disease Models, Animal; Dose-Response Relationship, Drug; GTP-Binding Protein alpha Subunits, Gq-G11/*metabolism; Gene Expression Regulation; Glucagon/blood/*secretion; Glucagon-Secreting Cells/*drug effects/enzymology/secretion; Liver/drug effects/metabolism; Male; Melanins/*pharmacology; Mice; Mice, Knockout; Pertussis Toxin/pharmacology; Phosphatidylinositol 3-Kinase/*metabolism; RNA, Messenger/metabolism; Rats; Rats, Wistar; Receptor, Melatonin, MT1/deficiency/*drug effects/genetics; Receptor, Melatonin, MT2/deficiency/*drug effects/genetics; Receptors, Glucagon/drug effects/genetics/metabolism; Signal Transduction/*drug effects; Tetrahydronaphthalenes/pharmacology; Tissue Culture Techniques; Tryptamines/pharmacology; Type C Phospholipases/metabolism|
Journal: Journal of pineal research Volume: 53 Issue: 4 Pages: 390-8 Date: June 8, 2012 PMID: 22672634 |
Bähr I, Mühlbauer E, Albrecht E, Peschke E (2012) Evidence of the receptor-mediated influence of melatonin on pancreatic glucagon secretion via the Gαq protein-coupled and PI3K signaling pathways. Journal of pineal research 53: 390-8.
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