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

NMDA 受体拮抗剂对人类 1 型糖尿病小鼠模型的胰岛素炎、β 细胞存活和再生的长期影响。

• 批准号: 434472323
• 负责人: Dr. Alena Welters, Ph.D.
• 金额: --
• 依托单位: Institut für Stoffwechselphysiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/434472323?language=en
• 关键词: Long; term; effects; NMDA; receptor

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.

1型糖尿病（T1 DM）是儿童最常见的慢性疾病之一。几十年来，它在许多欧洲国家的发病率一直在上升。在德国，约有31.500名儿童和青少年以及312.000名成人患有T1 DM。虽然已经有可能在非常早期的阶段识别出儿童患T1 DM的风险增加，但迄今为止还没有药物可持续地防止进行性β细胞破坏以阻止疾病进展。为了寻找新的抗糖尿病药物，我们开始研究胰腺N-甲基-D-天冬氨酸受体（NMDAR）在β细胞功能和胰岛细胞活力中的作用。我们首次证明了胰腺NMDAR的基因缺失或NMDAR拮抗剂右美沙芬（DXM）对NMDAR的药理学抑制增加了葡萄糖刺激的胰岛素分泌，改善了小鼠和男性的葡萄糖耐量，并增强了致糖尿病条件下胰岛细胞的存活率，无论是在体内的2型糖尿病小鼠模型db/db中还是在体外的分离的人胰岛中。基于我们之前的研究结果，我们现在正在研究NMDAR在人类T1 DM背景下的作用。我们的初步数据表明，在1型糖尿病小鼠模型NOD中，长期DXM治疗使糖尿病发病率降低了50%，保持了α和β细胞质量，并使胰岛数量显著增加了四倍以上。我们对分离的人类胰岛的研究进一步直接证明了我们发现的临床相关性，并增加了成功转化为基于人类的临床试验的机会。我们现在想研究DXM如何促进胰岛生理学的这些有益作用。DXM可能保护胰岛免受自身免疫介导的胰岛细胞破坏，或者促进β细胞增殖和/或诱导新生。考虑到分离的人CD 4 + T淋巴细胞表达功能性NMDAR，其表达在T细胞刺激后显著增加，我们进一步旨在研究DXM介导的对胰岛细胞存活的作用是否仅依赖于胰腺NMDAR的抑制或可能也依赖于NMDAR介导的自身免疫应答的修饰。因此，我们想研究致糖尿病药物链脲佐菌素在缺乏功能性胰腺NMDAR的小鼠中诱导糖尿病的效力。如果我们的体外和体内研究指出DXM调节细胞免疫应答的可能性，我们将比较健康志愿者和T1 DM儿童外周血（PBMC）分离单核细胞体外和离体T细胞克隆上NMDAR的表达和功能。我们的长期目标是开发一种新的，有效的和安全的抗糖尿病药物，延迟或防止进行性β细胞破坏，甚至在糖尿病表现后恢复葡萄糖稳态。