肥胖引起的糖尿病中神经线粒体和髓鞘脂质稳态的早期破坏

Early disruption of nerve mitochondrial and myelin lipid homeostasis in obesity-induced diabetes

Keywords：Demyelinating disorders; Diabetes; Metabolism; Neurological disorders; Neuroscience

关键词：脱髓鞘疾病; 糖尿病; 代谢; 神经系统疾病； 神经科学
作者：Juan P. Palavicini,Juan Chen,Chunyan Wang,Jianing Wang,Chao Qin,Eric Baeuerle,Xinming Wang, Jung A. Woo, David E. Kang,Nicolas Musi,Jeffrey L. Dupree, and Xianlin Han
出版期刊：《JCI insight》 2020/11/5

Abstract：

Diabetic neuropathy is a major complication of diabetes. Current treatment options alleviate pain but do not stop the progression of the disease. At present, there are no approved disease-modifying therapies. Thus, developing more effective therapies remains a major unmet medical need. Seeking to better understand the molecular mechanisms driving peripheral neuropathy, as well as other neurological complications associated with diabetes, we performed spatiotemporal lipidomics, biochemical, ultrastructural, and physiological studies on PNS and CNS tissue from multiple diabetic preclinical models. We unraveled potentially novel molecular fingerprints underlying nerve damage in obesity-induced diabetes, including an early loss of nerve mitochondrial (cardiolipin) and myelin signature (galactosylceramide, sulfatide, and plasmalogen phosphatidylethanolamine) lipids that preceded mitochondrial, myelin, and axonal structural/functional defects; started in the PNS; and progressed to the CNS at advanced diabetic stages. Mechanistically, we provided substantial evidence indicating that these nerve mitochondrial/myelin lipid abnormalities are (surprisingly) not driven by hyperglycemia, dysinsulinemia, or insulin resistance, but rather associate with obesity/hyperlipidemia. Importantly, our findings have major clinical implications as they open the door to novel lipid-based biomarkers to diagnose and distinguish different subtypes of diabetic neuropathy (obese vs. nonobese diabetics), as well as to lipid-lowering therapeutic strategies for treatment of obesity/diabetes-associated neurological complications and for glycemic control.

文章摘要：

糖尿病性神经病变是糖尿病的主要并发症。目前的治疗方案可以减轻疼痛，但不能阻止疾病的进展。目前，尚无批准的疾病改善疗法。因此，开发更有效的疗法仍然是未满足的主要医疗需求。为了更好地了解驱动周围神经病变的分子机制以及与糖尿病相关的其他神经系统并发症，我们对来自多个糖尿病临床前模型的 PNS 和 CNS 组织进行了时空脂质组学、生化、超微结构和生理学研究。我们揭示了肥胖引起的糖尿病中神经损伤的潜在新分子指纹，包括线粒体、髓磷脂和轴突结构/功能缺陷之前的神经线粒体（心磷脂）和髓磷脂特征（半乳糖神经酰胺、硫苷脂和缩醛磷脂磷脂酰乙醇胺）脂质的早期丧失;从 PNS 开始；并在糖尿病晚期进展到中枢神经系统。从机制上讲，我们提供了大量证据表明这些神经线粒体/髓鞘脂质异常（令人惊讶地）不是由高血糖、胰岛素异常或胰岛素抵抗驱动，而是与肥胖/高脂血症有关。重要的是，我们的研究结果具有重大的临床意义，因为它们为新的基于脂质的生物标志物打开了大门，以诊断和区分糖尿病神经病变的不同亚型（肥胖与非肥胖糖尿病患者），以及治疗肥胖的降脂治疗策略/糖尿病相关的神经系统并发症和血糖控制。 

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