Long-term effects of NMDA receptor antagonists on insulitis, beta cell survival and regeneration in mouse models of human type 1 diabetes mellitus.

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Type 1 Diabetes mellitus (T1DM) is one of the most common chronic disorders in children. Its incidence has been increasing in many European countries for several decades. In Germany, approximately 31.500 children and adolescents as well as 312.000 adults suffer from T1DM. Although it has become possible to identify children at an increased risk to develop T1DM at a very early stage, to date no medication exists that sustainably prevents progressive beta cell destruction to halt disease progression. In search of a new antidiabetic dug we started to investigate the role of pancreatic N-methyl-D-aspartate receptors (NMDARs) in beta cell function and islet cell viability. For the first time, we demonstrated that genetic deletion of pancreatic NMDARs or pharmacologic inhibition of NMDARs with the NMDAR antagonist Dextromethorphan (DXM) increases glucose-stimulated insulin secretion, improves glucose tolerance in mice and men and enhances islet cell survival under diabetogenic conditions, both in the type 2 diabetic mouse model db/db in vivo and in isolated human pancreatic islets in vitro. Based on our previous findings we are now investigating the role of NMDARs in the context of human T1DM. Our preliminary data indicate, that in the type 1 diabetic mouse model NOD, long-term DXM treatment reduces diabetes incidence by 50%, maintains alpha- and beta-cell mass and significantly increases the number of pancreatic islets more than fourfold. Our studies on isolated human pancreatic islets furthermore directly proof the clinical relevance of our findings and increase the chance of a successful translation to human-based clinical trials. We now want to investigate how DXM promotes these beneficial effects on islet physiology. It is possible that DXM protects pancreatic islets against autoimmune-mediated islet cell destruction or that it promotes beta cell proliferation and/or induces neogenesis. Given that isolated human CD4+ T-lymphocytes express functional NMDAR whose expression significantly increases upon T-cell stimulation we furthermore aim to investigate whether the DXM-mediated effects on islet cell survival are solely dependent on the inhibition of pancreatic NMDARs or possibly also on the NMDAR-mediated modification of the autoimmune response. We therefore want to study the potency of the diabetogenic agent streptozotocin to induce diabetes in mice that lack functional pancreatic NMDARs. In case our in vitro and in vivo studies point to the possibility that DXM modulates cellular immune response we will compare the expression and function of NMDARs on T-cell clones in vitro and ex vivo on isolated mononuclear cells of the peripheral blood (PBMCs) from healthy volunteers and from children with T1DM. Our long-term goal is the development of a new, potent and safe anti-diabetic medication that delays or prevents progressive beta cell destruction, or that even restores glucose homeostasis after diabetes manifestation.