Interaction between magnesium and methylglyoxal in diabetic polyneuropathy and neuronal models
| Autor: | Martin Schmuck, Alexander Strom, Mark A. Yorek, Karsten Müssig, Hanna Shevalye, Dan Ziegler, F Zivehe, Klaus Strassburger, Eric P. Davidson, Bengt-Frederik Belgardt, Volker Burkart, Rudolph Reimer, Michael Roden, Peter P. Nawroth, Gidon J. Bönhof, Thomas Fleming, Barbara Biermann, Julia Szendroedi, Ellen Fritsche |
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| Rok vydání: | 2021 |
| Předmět: |
Glycation End Products
Advanced Male 0301 basic medicine GLO2 Glyoxalase 2 AGEs Advanced glycation end-products Type 2 diabetes Nerve conduction velocity Mice chemistry.chemical_compound 0302 clinical medicine Diabetic Neuropathies Magnesium deficiency (medicine) Magnesium GDS German Diabetes Study Neurons Methylglyoxal Carbonyl stress Middle Aged Pyruvaldehyde Mitochondria TDT thermal detection threshold Female Original Article GLO1 glyoxalase 1 Sensorimotor Cortex medicine.medical_specialty DSPN diabetic sensorimotor polyneuropathy 030209 endocrinology & metabolism Neuroprotection Hypomagnesemia Polyneuropathies 03 medical and health sciences Diabetes mellitus Internal medicine Diabetes Mellitus medicine Animals Humans Diabetic sensorimotor polyneuropathy Molecular Biology business.industry Neurotoxicity Cell Biology medicine.disease PDH pyruvate dehydrogenase DRG dorsal root ganglia Cross-Sectional Studies 030104 developmental biology Endocrinology chemistry BSA bovine serum albumin PFA paraformaldehyde Energy Metabolism business Recent-onset type 2 diabetes |
| Zdroj: | Molecular Metabolism |
| ISSN: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2020.101114 |
| Popis: | Objective The lack of effective treatments against diabetic sensorimotor polyneuropathy demands the search for new strategies to combat or prevent the condition. Because 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, the 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. Highlights • Magnesium and methylglyoxal levels were inversely associated in individuals with type 2 diabetes and distal sensorimotor polyneuropathy. • Magnesium, methylglyoxal, and their interaction were associated with methylglyoxal-dependent nerve dysfunction. • Under experimental conditions, magnesium supplementation prevented methylglyoxal-mediated neurotoxicity. • Magnesium downregulates intracellular methylglyoxal production. |
| Databáze: | OpenAIRE |
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