Objective

The lack of effective treatments against diabetic sensorimotor polyneuropathy demands the search for new strategies to combat or prevent the condition. Since reduced magnesium and increased methylglyoxal levels have been implicated in the development of both type 2 diabetes and neuropathic pain, we aimed to assess the putative interplay of both molecules with diabetic sensorimotor polyneuropathy.

Methods

In a cross-sectional study serum magnesium and plasma methylglyoxal levels were measured in recently diagnosed type 2 diabetes patients with (n=51) and without (n=184) diabetic sensorimotor polyneuropathy from the German Diabetes Study baseline cohort. Peripheral nerve function was assessed using nerve conduction velocity and quantitative sensory testing. Human neuroblastoma cells (SH-SY5Y) and mouse dorsal root ganglia cells were used to characterize the neurotoxic effect of methylglyoxal and/or neuroprotective effect of magnesium.

Results

Here we demonstrate that serum magnesium concentration was reduced in recently diagnosed type 2 diabetes patients with diabetic sensorimotor polyneuropathy and inversely associated with plasma methylglyoxal concentration. Magnesium, methylglyoxal, and importantly their interaction were strongly interrelated with methylglyoxal-dependent nerve dysfunction and were predictive of changes in nerve function. Magnesium supplementation prevented methylglyoxal neurotoxicity in differentiated SH-SY5Y neuron-like cells due to reduction of intracellular methylglyoxal formation, while supplementation with the divalent cations zinc and manganese had no effect on methylglyoxal neurotoxicity. Furthermore, downregulation of mitochondrial activity in mouse dorsal root ganglia cells and consequently the enrichment of triosephosphates, the primary source of methylglyoxal, resulted in neurite degeneration, which was completely prevented through magnesium supplementation.

Conclusions

These multifaceted findings reveal a novel putative pathophysiological pathway of hypomagnesemia-induced carbonyl stress leading to neuronal damage and merit further investigations not only for diabetic sensorimotor polyneuropathy but also other neurodegenerative diseases associated with magnesium deficiency and impaired energy metabolism.

中文翻译：

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糖尿病多发性神经病和神经元模型中镁和甲基乙二醛的相互作用

客观的

缺乏针对糖尿病感觉运动性多发性神经病的有效治疗方法，需要寻找新的策略来对抗或预防这种情况。由于减少的镁和增加的甲基乙二醛水平与 2 型糖尿病和神经性疼痛的发展有关，我们旨在评估这两种分子与糖尿病感觉运动性多发性神经病的假定相互作用。

方法

在一项横断面研究中，测量了来自德国糖尿病研究基线队列的最近诊断为 (n=51) 和没有 (n=184) 糖尿病感觉运动性多发性神经病的 2 型糖尿病患者的血清镁和血浆甲基乙二醛水平。使用神经传导速度和定量感觉测试评估外周神经功能。人类神经母细胞瘤细胞 (SH-SY5Y) 和小鼠背根神经节细胞用于表征甲基乙二醛的神经毒性作用和/或镁的神经保护作用。

结果

在这里，我们证明了最近诊断出的患有糖尿病感觉运动性多发性神经病的 2 型糖尿病患者的血清镁浓度降低，并且与血浆甲基乙二醛浓度呈负相关。镁、甲基乙二醛以及重要的它们的相互作用与甲基乙二醛依赖性神经功能障碍密切相关，并且可以预测神经功能的变化。由于细胞内甲基乙二醛的形成减少，镁补充剂可防止分化的 SH-SY5Y 神经元样细胞中的甲基乙二醛神经毒性，而补充二价阳离子锌和锰对甲基乙二醛神经毒性没有影响。此外，下调小鼠背根神经节细胞线粒体活性，从而富集磷酸丙糖，

结论

这些多方面的发现揭示了低镁血症诱导的羰基应激导致神经元损伤的一种新的假定病理生理学途径，值得进一步研究，不仅适用于糖尿病性感觉运动性多发性神经病，还适用于与镁缺乏和能量代谢受损相关的其他神经退行性疾病。