Saxon Academy of science Leipzig

Leipzig, Germany

Saxon Academy of science Leipzig

Leipzig, Germany

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Bazwinsky-Wutschke I.,Martin Luther University of Halle Wittenberg | Muhlbauer E.,Saxon Academy of science Leipzig | Albrecht E.,Martin Luther University of Halle Wittenberg | Peschke E.,Martin Luther University of Halle Wittenberg
Journal of Pineal Research | Year: 2014

The pineal secretory product melatonin exerts its influence on the insulin secretion of pancreatic islets by different signaling pathways. The purpose of this study was to analyze the impact of melatonin on calcium-signaling components under different conditions. In a transfected INS-1 cell line overexpressing the human MT2 receptor (hMT2-INS-1), melatonin treatment induced even stronger depressive effects on calcium/calmodulin-dependent kinase 2d and IV (Camk2d, CamkIV) transcripts during 3-isobutyl-1-methylxanthine (IBMX) treatment than in normal INS-1 cells, indicating a crucial influence of melatonin receptor density on transcript-level regulation. In addition, melatonin induced a significant downregulation of calmodulin (Calm1) in IBMX-treated hMT2-INS-1 cells. Long-term administration of melatonin alone reduced CamkIV transcript levels in INS-1 cells; however, transcript levels of Camk2d remained unchanged. The release of insulin was diminished under long-term melatonin treatment. The impact of melatonin also involved reductions in CAMK2D protein during IBMX or forskolin treatments in INS-1 cells, as measured by an enzyme-linked immunosorbent assay, indicating a functional significance of transcriptional changes in pancreatic islets. Furthermore, analysis of melatonin receptor knockout mice showed that the transcript levels of Camk2d, CamkIV, and Calm1 were differentially influenced according to the melatonin receptor subtype deleted. In conclusion, this study provides evidence that melatonin has different impacts on the regulation of Calm1 and Camk. These calcium-signaling components are known as participants in the calcium/calmodulin pathway, which plays an important functional role in the modulation of the β-cell signaling pathways leading to insulin secretion. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Zibolka J.,Martin Luther University of Halle Wittenberg | Muhlbauer E.,Saxon Academy of science Leipzig | Peschke E.,Saxon Academy of science Leipzig
Journal of Pineal Research | Year: 2015

Melatonin is an effector of the diurnal clock on pancreatic islets. The membrane receptor-transmitted inhibitory influence of melatonin on insulin secretion is well established and contrasts with the reported stimulation of glucagon release from α-cells. Virtually, nothing is known concerning the melatonin-mediated effects on islet δ-cells. Analysis of a human pancreatic δ-cell model, the cell line QGP-1, and the use of a somatostatin-specific radioimmunoassay showed that melatonin primarily has an inhibitory effect on somatostatin secretion in the physiological concentration range. In the pharmacological range, melatonin elicited slightly increased somatostatin release from δ-cells. Cyclic adenosine monophosphate (cAMP) is the major second messenger dose-dependently stimulating somatostatin secretion, in experiments employing the membrane-permeable 8-Br-cAMP. 8-Br-cyclic guanosine monophosphate proved to be of only minor relevance to somatostatin release. As the inhibitory effect of 1 nm melatonin was reversed after incubation of QGP-1 cells with the nonselective melatonin receptor antagonist luzindole, but not with the MT2-selective antagonist 4-P-PDOT (4-phenyl-2-propionamidotetraline), an involvement of the MT1 receptor can be assumed. Somatostatin release from the δ-cells at low glucose concentrations was significantly inhibited during co-incubation with 1 nm melatonin, an effect which was less pronounced at higher glucose levels. Transient expression experiments, overexpressing MT1, MT2, or a deletion variant as a control, indicated that the MT1 and not the MT2 receptor was the major transmitter of the inhibitory melatonin effect. These data point to a significant influence of melatonin on pancreatic δ-cells and on somatostatin release. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Bazwinsky-Wutschke I.,Martin Luther University of Halle Wittenberg | Bieseke L.,Martin Luther University of Halle Wittenberg | Muhlbauer E.,Saxon Academy of science Leipzig | Peschke E.,Martin Luther University of Halle Wittenberg
Journal of Pineal Research | Year: 2014

The pineal hormone melatonin is known to influence insulin secretion via the G-protein-coupled receptor isoforms MT1 and MT2. The present study was aimed to further elucide the impact of melatonin on blood glucose regulation. To this end, mouse lines were used, in which one of the two or both melatonin receptors were deleted. In comparison with wild-type mice of the same age (8-12 months old), increased plasma insulin and melatonin levels and decreased blood glucose levels and body weights were detected in the MT1- and double-knockout lines. The elimination of melatonin receptor signalling also altered blood glucose concentrations, body weight and melatonin and insulin levels when comparing wild-type and receptor knockout mice of different ages (6 wk and 8-12 months old); such changes, however, were dependent on the type of receptor deleted. Furthermore, reverse transcription polymerase chain reaction results provided evidence that melatonin receptor deficiency has an impact on transcript levels of pancreatic islet hormones as well as on pancreatic and hepatic glucose transporters (Glut1 and 2). Under stimulated insulin secretion in the presence of melatonin in the rat insulinoma β-cells INS-1, the Glut1 transcript level was decreased. In conclusion, the present findings demonstrate that melatonin receptor knockout types affect blood glucose levels, body weight, plasma levels of melatonin and insulin, as well as pancreatic hormone and Glut1 expression in significantly different manners. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Peschke E.,Martin Luther University of Halle Wittenberg | Muhlbauer E.,Saxon Academy of science Leipzig
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2010

Glucose triggers insulin secretion of the pancreatic β-cells. The pineal hormone melatonin interferes in this process by inhibiting secretion and transmitting circadian timing information to the islets. Circadian insulin secretion is adapted to day/night changes through melatonin-dependent synchronization. In rats and mice, melatonin levels are high during the dark period, which is their active feeding period, while, in humans, melatonin levels are high during the overnight fasting and sleeping period. This implies a different read-out of melatonin signaling in day-active species, including man. Dysregulation of circadian secretion may be a key to the increase of type 2 diabetes (T2D). This review discusses the impact of melatonin on insulin secretion transmitted through both the pertussis-toxin-sensitive membrane receptors MT1 (MTNR1a) and MT2 (MTNR1b) and the second messengers cAMP, cGMP and IP3. This is an important topic since, in several genetic association studies, single nucleotide polymorphisms of the human MT2-receptor have been described as being causally linked with an elevated risk of developing T2D. This article summarizes interrelationships between melatonin and insulin in type 1 diabetic (T1D) and type 2 diabetic (T2D) rats and humans. © 2010 Published by Elsevier Ltd.


Peschke E.,Saxon Academy of science Leipzig | Bahr I.,Martin Luther University of Halle Wittenberg | Muhlbauer E.,Saxon Academy of science Leipzig
Journal of Pineal Research | Year: 2015

The pineal hormone melatonin influences insulin secretion, as well as glucagon and somatostatin secretion, both in vivo and in vitro. These effects are mediated by two specific, high-affinity, seven transmembrane, pertussis toxin-sensitive, Gi-protein-coupled melatonin receptors, MT1 and MT2. Both isoforms are expressed in the β-cells, α-cells as well as δ-cells of the pancreatic islets of Langerhans and are involved in the modulation of insulin secretion, leading to inhibition of the adenylate cyclase-dependent cyclic adenosine monophosphate as well as cyclic guanosine monophosphate formation in pancreatic β-cells by inhibiting the soluble guanylate cyclase, probably via MT2 receptors. In this way, melatonin also likely inhibits insulin secretion, whereas using the inositol triphosphate pathway after previous blocking of Gi-proteins by pertussis toxin, melatonin increases insulin secretion. Desynchrony of receptor signaling may lead to the development of type 2 diabetes. This notion has recently been supported by genomewide association studies pinpointing variances of the MT2 receptor as a risk factor for this rapidly spreading metabolic disturbance. As melatonin is secreted in a clearly diurnal fashion, it is safe to assume that it also has a diurnal impact on the blood-glucose-regulating function of the islet. Observations of the circadian expression of clock genes (Clock, Bmal1, Per1,2,3, and Cry1,2) in pancreatic islets, as well as in INS1 rat insulinoma cells, may indicate that circadian rhythms are generated in the β-cells themselves. The circadian secretion of insulin from pancreatic islets is clock-driven. Disruption of circadian rhythms and clock function leads to metabolic disturbances, for example, type 2 diabetes. The study of melatonin-insulin interactions in diabetic rat models has revealed an inverse relationship between these two hormones. Both type 2 diabetic rats and patients exhibit decreased melatonin levels and slightly increased insulin levels, whereas type 1 diabetic rats show extremely reduced levels or the absence of insulin, but statistically significant increases in melatonin levels. Briefly, an increase in melatonin levels leads to a decrease in stimulated insulin secretion and vice versa. Melatonin levels in blood plasma, as well as the activity of the key enzyme of melatonin synthesis, AA-NAT (arylalkylamine-N-acetyltransferase) in pineal, are lower in type 2 diabetic rats compared to controls. In contrast, melatonin and pineal AA-NAT mRNA are increased and insulin receptor mRNA is decreased in type 1 diabetic rats, which also indicates a close relationship between insulin and melatonin. As an explanation, it was hypothesized that catecholamines, which reduce insulin levels and stimulate melatonin synthesis, control insulin-melatonin interactions. This conviction stems from the observation that catecholamines are increased in type 1 but are diminished in type 2 diabetes. In this context, another important line of inquiry involves the fact that melatonin protects β-cells against functional overcharge and, consequently, hinders the development of type 2 diabetes. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Muhlbauer E.,Saxon Academy of science Leipzig | Bazwinsky-Wutschke I.,Martin Luther University of Halle Wittenberg | Wolgast S.,Saxon Academy of science Leipzig | Labucay K.,Martin Luther University of Halle Wittenberg | Peschke E.,Martin Luther University of Halle Wittenberg
Molecular and Cellular Endocrinology | Year: 2013

The retinoic-acid-related receptor family of orphan receptors (RORs) act as transcriptional activators or repressors. One of their functions involves integrated actions within circadian oscillators, particularly of the periphery. The present paper describes differential expression of the orphan receptors RORα, RORβ and RORγ and of the nuclear retinoid receptor RXRα in the pancreas and islet of rats. Immunohistochemistry of rodent islets detected nuclear receptor expression. The RORα and RORβ signals were visualised in α-cells, whereas that of RORγ was largely confined to β-cells. RXRα was expressed throughout the islets. Quantitative RT-PCR revealed circadian expression in the rat pancreas for RORγ, RORα and RXRα, but not for RORβ. Circadian expression of RORγ mRNA was verified in mouse pancreas and in rat INS-1 β cells by serum shock experiments. The results point to differential and circadian expression and thus cell-type-specific functions of RORα and RORγ in islet cells secreting glucagon or insulin. © 2012 Elsevier Ireland Ltd.


Bazwinsky-Wutschke I.,Martin Luther University of Halle Wittenberg | Wolgast S.,Saxon Academy of science Leipzig | Muhlbauer E.,Saxon Academy of science Leipzig | Peschke E.,Martin Luther University of Halle Wittenberg
Histochemistry and Cell Biology | Year: 2010

The present study dealt with the localization of different calcium-binding proteins (CaBPs) in the pancreatic tissue of non-diabetic and diabetic rats and in rat insulinoma β-cells (INS-1). Transcripts of CaBPs displayed different expression levels in rat pancreatic tissue and INS-1 cells. Immunohistochemistry demonstrated that three of these proteins, calmodulin, calreticulin and calbindin-D28k, were located predominantly in the pancreatic islets (in both α-and β-cells) of rats, showing weaker labeling of exocrine tissue. Secretagogin was exclusively found within islets. All CaBPs were also immunohistochemically detected in INS-1 cells. Immunohistochemical analysis demonstrates differences in CaBP distributions when comparing the pancreatic tissues of diabetic Goto-Kakizaki rats and non-diabetic Wistar rats. Pancreatic tissue in type 2 diabetic Goto-Kakizaki rats showed significantly higher transcript levels of all CaBPs compared to those in Wistar rats. These results indicate that alterations of CaBPs in pancreatic islets are associated with metabolic disturbances related to type 2 diabetes. © Springer-Verlag 2010.


Muhlbauer E.,Saxon Academy of science Leipzig | Albrecht E.,Martin Luther University of Halle Wittenberg | Bazwinsky-Wutschke I.,Martin Luther University of Halle Wittenberg | Peschke E.,Martin Luther University of Halle Wittenberg
Journal of Pineal Research | Year: 2012

Several studies have revealed that melatonin affects the insulin secretion via MT 1 and MT 2 receptor isoforms. Owing to the lack of selective MT 1 receptor antagonists, we used RNA interference technology to generate an MT 1 knockdown in a clonal β-cell line to evaluate whether melatonin modulates insulin secretion specifically via the MT 1 receptor. Incubation experiments were carried out, and the insulin concentration in supernatants was measured using a radioimmunoassay. Furthermore, the intracellular cAMP was determined using an enzyme-linked immunosorbent assay. Real-time RT-PCR indicated that MT 1 knockdown resulted in a significant increase in the rIns1 mRNA and a significantly elevated basal insulin secretion of INS-1 cells. Incubation with melatonin decreased the amount of glucagon-like peptide 1 or inhibited the glucagon-stimulated insulin release of INS-1 cells, while, in MT 1-knockdown cells, no melatonin-induced reduction in insulin secretion could be found. No decrease in 3-isobutyl-1-methylxanthine-stimulated intracellular cAMP in rMT 1-knockdown cells was detectable after treatment with melatonin either, and immunocytochemistry proved that MT 1 knockdown abolished phosphorylation of cAMP-response-element- binding protein. In contrast to the INS-1 cells, preincubation with melatonin did not sensitize the insulin secretion of rMT 1-knockdown cells. We also monitored insulin secretion from isolated islets of wild-type and melatonin-receptor knockout mice ex vivo. In islets of wild-type mice, melatonin treatment resulted in a decrease in insulin release, whereas melatonin treatment of islets from MT 1 knockout and MT 1/2 double-knockout mice did not show a significant effect. The data indicate that melatonin inhibits insulin secretion, primarily via the MT 1 receptor in rat INS-1 cells and isolated mouse islets. © 2011 John Wiley & Sons A/S.


Bach A.G.,Martin Luther University of Halle Wittenberg | Muhlbauer E.,Saxon Academy of science Leipzig | Peschke E.,Martin Luther University of Halle Wittenberg
Endocrinology | Year: 2010

A decrease in the nighttime release of the pineal hormone melatonin is associated with aging and chronic diseases in animals an humans. Melatonin has a protective role in type 2 diabetes; however, its synthesis itself is affected in the disease. The aim of this study was to detect crucially impaired steps in the pineal melatonin synthesis of type 2 diabetic Goto-Kakizaki (GK) rats. Therefore, plasma melatonin concentrations and the pineal content of melatonin and its precursors (tryptophan, 5-hydroxytryptophan, serotonin, and N-acetylserotonin) were quantified in GK rats compared with Wistar rats (each group 8 and 50 wk old) in a diurnal manner (four animals per group and per time point). Additionally, the expression of pineal adrenoceptor subtype mRNA was investigated. We found that in diabetic GK rats, 1) inhibitory α-2-adrenoceptors are significantly more strongly expressed than in Wistar rats, 2) the formation of 5-hydroxytryptophan is crucially impaired, and 3) the pineal gland protein content is significantly reduced compared with that in Wistar rats. This is the first time that melatonin synthesis is examined in a type 2 diabetic rat model in a diurnal manner. The present data unveil several reasons for a reduced melatonin secretion in diabetic animals and present an important link in the interaction between melatonin and insulin. Copyright © 2010 by The Endocrine Society.


Bahr I.,Martin Luther University of Halle Wittenberg | Muhlbauer E.,Saxon Academy of science Leipzig | Albrecht E.,Martin Luther University of Halle Wittenberg | Peschke E.,Martin Luther University of Halle Wittenberg
Journal of Pineal Research | Year: 2012

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 α-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 α-cell line αTC1 clone 9 (αTC1.9) as well as isolated pancreatic islets of rats and mice revealed that melatonin increases glucagon secretion. Preincubation of αTC1.9 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 Gαi- and Gαs-coupled signaling cascades in mediating the glucagon increase induced by melatonin. In contrast, inhibition of phospholipase C in αTC1.9 cells prevented the melatonin-induced effect, indicating the physiological relevance of the Gαq-coupled pathway. Our data point to the involvement of the phosphatidylinositol 3-kinase signaling cascade in mediating melatonin effects in pancreatic α-cells. In conclusion, these findings provide evidence that the glucagon-stimulatory effect of melatonin in pancreatic α-cells is melatonin receptor mediated, thus supporting the concept of melatonin-modulated and diurnal glucagon release. © 2012 John Wiley & Sons A/S.

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