Long-term effects of NMDA receptor antagonists on insulitis, beta cell survival and regeneration in mouse models of human type 1 diabetes mellitus.
Final Report Abstract
Type 1 diabetes mellitus (T1DM) is the most common metabolic disease in children and adolescents. Despite various technical achievements in recent years, such as the development of continuous glucose monitoring and automated insulin delivery (AID) systems, the treatment of T1DM still requires the lifelong administration of exogenous insulin. The new staging of T1DM enables pre-symptomatic diagnosis by determining diabetes-specific autoantibodies. At this stage, the use of an immunomodulatory and/or beta-cell-protective drug is possible. However, there is currently no drug available that can efficiently and permanently prevent the manifestation of T1DM, despite intensive research. Our research group investigates the role of pancreatic NMDA receptors in insulin secretion, glucose tolerance, and the viability of the islets of Langerhans using various in vitro and in vivo models. We have demonstrated that inhibition of pancreatic NMDA receptors mediates islet cell protection under diabetogenic conditions in vitro and in a mouse model for type 2 diabetes mellitus. Preclinical and clinical studies from other research groups suggest that NMDAR antagonists possess anti-inflammatory and immunomodulatory properties. Therefore, the aim of this project was to investigate the effect of NMDA receptor antagonists on glucose homeostasis, pancreatic islet inflammation (insulitis), and beta cell survival in the context of autoimmune-mediated T1DM. To achieve this, we continuously administered dextromethorphan (DXM), an NMDA receptor antagonist, to NOD mice via their drinking water. The data demonstrate that DXM enhances glucose homeostasis and reduces diabetes incidence by 50% in NOD mice. Additionally, DXM promotes pancreatic islet cell survival in NOD mice, resulting in five-fold higher numbers of pancreatic islets and more than two-fold larger alpha and beta cell areas compared to untreated NOD mice. The mechanisms underlying these effects are not yet fully understood. In vitro, treatment with dextrorphan, the active metabolite of DXM, reduced pancreatic islet chemokine expression. However, in NOD mice, we could not demonstrate a significant effect of DXM on the extent of insulitis, despite the fact that the infiltration of islets of Langerhans with CD4- and CD8-positive T lymphocytes was reduced by 60% with DXM treatment. In conclusion, our data suggest that DXM may be a novel candidate for adjunctive treatment of preclinical or recent-onset T1DM. DXM has been used clinically for over 50 years, and therapeutic doses of DXM are safe, even in children and adolescents. Furthermore, there is preclinical and clinical evidence that DXM is protective against angio-, retino-, and nephropathy, which would be an additional benefit in the treatment of individuals with diabetes mellitus.
Publications
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Novel Approaches to Restore Pancreatic Beta-Cell Mass and Function. Handbook of Experimental Pharmacology, 439-465. Springer International Publishing.
Welters, Alena & Lammert, Eckhard
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Peripherally active dextromethorphan derivatives lower blood glucose levels by targeting pancreatic islets. Cell Chemical Biology, 28(10), 1474-1488.e7.
Scholz, Okka; Otter, Silke; Welters, Alena; Wörmeyer, Laura; Dolenšek, Jurij; Klemen, Maša Skelin; Pohorec, Viljem; Eberhard, Daniel; Mrugala, Jessica; Hamacher, Anna; Koch, Angela; Sanz, Miguel; Hoffmann, Torsten; Hogeback, Jens; Herebian, Diran; Klöcker, Nikolaj; Piechot, Alexander; Mayatepek, Ertan; Meissner, Thomas ... & Lammert, Eckhard
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The N-Methyl-D-Aspartate Receptor Antagonist Dextromethorphan Improves Glucose Homeostasis and Preserves Pancreatic Islets in NOD Mice. Hormone and Metabolic Research, 56(03), 223-234.
Wörmeyer, Laura; Nortmann, Oliver; Hamacher, Anna; Uhlemeyer, Celina; Belgardt, Bengt; Eberhard, Daniel; Mayatepek, Ertan; Meissner, Thomas; Lammert, Eckhard & Welters, Alena
