Decreased glycolytic and tricarboxylic acid cycle intermediates coincide with peripheral nervous system oxidative stress in a murine model of type 2 diabetes.
Decreased glycolytic and tricarboxylic acid cycle intermediates coincide with peripheral nervous system oxidative stress in a murine model of type 2 diabetes.
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DOI：
10.1530/joe-12-0356
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发表时间：
2013-01
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影响因子：
--
通讯作者：
Feldman EL
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作者：
Hinder LM;Vivekanandan-Giri A;McLean LL;Pennathur S;Feldman EL
糖尿病神经病变（DN）是糖尿病最常见的并发症，其特征是周围神经轴突从远端到近端的缺失。糖尿病并发症易发组织中能量代谢的组织特异性病理改变的想法正在出现。在1型糖尿病模型中观察到神经代谢改变;然而，基于这些模型的治疗策略对2型糖尿病DN患者的疗效有限。因此，了解周围神经如何代谢适应独特的2型糖尿病环境对于开发疾病改善治疗至关重要。在本研究中，我们利用靶向LC/MS/MS来表征来自雄性2型糖尿病小鼠（BKS.Cg-m+/+Leprdb; db/db）和对照（db/+）的腓肠神经、坐骨神经和背根神经节（DRG）中的糖酵解和三羧酸（TCA）循环代谢组。我们报告了糖尿病腓肠神经和坐骨神经中糖酵解中间产物（葡萄糖-6-磷酸、果糖-6-磷酸、果糖-1，6-二磷酸（仅腓肠神经）、3-磷酸甘油酸、2-磷酸甘油酸、磷酸烯醇丙酮酸、乳酸）的耗竭，而DRG无显著变化。糖尿病小鼠腓肠神经、坐骨神经和DRG中柠檬酸和异柠檬酸TCA循环中间产物减少。利用LC/ESI/MS/MS和HPLC方法，我们还观察到db/db组织中蛋白质和脂质氧化（硝基酪氨酸;羟基十八碳二烯酸，HODE）增加，氧化应激从近端到远端增加，并伴有乌头酸酶活性降低。我们提出了一个初步的模型，即代谢组学特征的变化，氧化应激的增加，TCA循环酶活性的降低可能会导致远端外周神经依赖于2型糖尿病环境中截短的TCA循环代谢。
Diabetic neuropathy (DN) is the most common complication of diabetes and is characterized by distal-to-proximal loss of peripheral nerve axons. The idea of tissue-specific pathological alterations in energy metabolism in diabetic complications-prone tissues is emerging. Altered nerve metabolism in type 1 diabetes models is observed; however, therapeutic strategies based on these models offer limited efficacy to type 2 diabetic patients with DN. Therefore, understanding how peripheral nerves metabolically adapt to the unique type 2 diabetic environment is critical to develop disease-modifying treatments. In the current study, we utilized targeted LC/MS/MS to characterize the glycolytic and tricarboxylic acid (TCA) cycle metabolomes in sural nerve, sciatic nerve and dorsal root ganglia (DRG) from male type 2 diabetic mice (BKS.Cg-m+/+Leprdb; db/db) and controls (db/+). We report depletion of glycolytic intermediates in diabetic sural nerve and sciatic nerve (glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-bisphosphate (sural nerve only), 3-phosphoglycerate, 2-phosphoglycerate, phosphoenolpyruvate, lactate), with no significant changes in DRG. Citrate and isocitrate TCA cycle intermediates were decreased in sural nerve, sciatic nerve and DRG from diabetic mice. Utilizing LC/ESI/MS/MS and HPLC methods, we also observed increased protein and lipid oxidation (nitrotyrosine; hydroxyoctadecadienoic acids, HODEs) in db/db tissue, with a proximal-to-distal increase in oxidative stress, with associated decreased aconitase enzyme activity. We propose a preliminary model, whereby the greater change in metabolomic profile, increase in oxidative stress, and decrease in TCA cycle enzyme activity may cause distal peripheral nerve to rely on truncated TCA cycle metabolism in the type 2 diabetes environment.