Düsseldorf, Germany
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Marquard J.,Heinrich Heine University Düsseldorf | Marquard J.,University Childrens Hospital Dusseldorf | Otter S.,Heinrich Heine University Düsseldorf | Otter S.,Institute for Beta Cell Biology | And 34 more authors.
Nature Medicine | Year: 2015

In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca 2+ concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.

Marquard J.,Heinrich Heine University Düsseldorf | Marquard J.,University Childrens Hospital Dusseldorf | Stirban A.,Profil | Schliess F.,Profil | And 15 more authors.
Diabetes, Obesity and Metabolism | Year: 2016

In this clinical trial, we investigated the blood glucose (BG)-lowering effects of 30, 60 and 90 mg dextromethorphan (DXM) as well as 100 mg sitagliptin alone versus combinations of DXM and sitagliptin during an oral glucose tolerance test (OGTT) in 20 men with T2DM. The combination of 60 mg DXM plus 100 mg sitagliptin was observed to have the strongest effect in the OGTT. It lowered maximum BG concentrations and increased the baseline-adjusted area under the curve for serum insulin concentrations in the first 30 min of the OGTT (mean ± standard deviation 240 ± 47 mg/dl and 8.1 ± 6.1 mU/l/h, respectively) to a significantly larger extent than did 100 mg sitagliptin alone (254 ± 50 mg/dl and 5.8 ± 2.5 mU/l/h, respectively; p < 0.05) and placebo (272 ± 49 mg/dl and 3.9 ± 3.0 mU/l/h, respectively; p < 0.001). All study drugs were well tolerated, alone and in combination, without serious adverse events or hypoglycaemia. Long-term clinical trials are now warranted to investigate the potential of the combination of 30 or 60 mg DXM and dipeptidyl peptidase-4 inhibitors in the treatment of individuals with T2DM, in particular as preclinical studies have identified the β-cell protective properties of DXM. © 2016 John Wiley & Sons Ltd.

Otter S.,Heinrich Heine University Düsseldorf | Otter S.,Institute for Beta Cell Biology | Lammert E.,Heinrich Heine University Düsseldorf | Lammert E.,Institute for Beta Cell Biology
Trends in Endocrinology and Metabolism | Year: 2016

Glutamate represents a key excitatory neurotransmitter in the central nervous system, and also modulates the function and viability of endocrine cells in pancreatic islets. In insulin-secreting beta cells, glutamate acts as an intracellular messenger, and its transport into secretory granules promotes glucose- and incretin-stimulated insulin secretion. Mitochondrial degradation of glutamate also contributes to insulin release when glutamate dehydrogenase is allosterically activated. It also signals extracellularly via glutamate receptors (AMPA and NMDA receptors) to modulate glucagon, insulin and somatostatin secretion, and islet cell survival. Its degradation products, GABA and γ-hydroxybutyrate, are released and also influence islet cell behavior. Thus, islet glutamate receptors, such as the NMDA receptors, might serve as possible drug targets to develop new medications for adjunct treatment of diabetes. © 2015 Elsevier Ltd.

Neufeld S.,Heinrich Heine University Düsseldorf | Planas-Paz L.,Heinrich Heine University Düsseldorf | Lammert E.,Heinrich Heine University Düsseldorf | Lammert E.,Institute for Beta Cell Biology
Seminars in Cell and Developmental Biology | Year: 2014

The blood and lymphatic vasculatures are essential for nutrient delivery, gas exchange and fluid homeostasis in all tissues of higher vertebrates. They are composed of a hierarchical network of vessels, which are lined by vascular or lymphatic endothelial cells. For blood vascular lumen formation to occur, endothelial cell cords polarize creating apposing apical cell surfaces, which repulse each other and give rise to a small intercellular lumen. Following cell shape changes, the vascular lumen expands. Various junctional proteins, polarity complexes, extracellular matrix binding and actin remodelling molecules are required for blood vascular lumen formation. In contrast, little is known regarding the molecular mechanisms leading to lymphatic vascular tube formation. Current models agree that lymphatic vessels share a blood vessel origin, but they differ in identifying the mechanism by which a lymphatic lumen is formed. A ballooning mechanism was proposed, in which lymph sacs are connected via their lumen to the cardinal veins. Alternatively, a mechanism involving budding of streams of lymphatic endothelial cells from either the cardinal veins or both the cardinal veins and the intersomitic vessels, and subsequent assembly and lumenisation was recently described. Here, we discuss what is currently known about the molecular and cellular machinery that guides blood and lymphatic vascular tube formation in mouse. © 2014 Elsevier Ltd.

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