小柯机器人

2023年1月25日，《自然》杂志在线发表了美国科学家的一项最新研究成果。来自加州大学圣迭戈的Christian M. Metallo研究小组发现，胰岛素调节的丝氨酸和脂代谢驱动周围神经病变。

研究人员证明了异常的丝氨酸稳态驱动糖尿病小鼠的丝氨酸和甘氨酸缺乏，这可以通过量化丝氨酸摄取和处理的丝氨酸耐受试验来诊断。通过限制饮食中的丝氨酸或甘氨酸以及高脂肪摄入来模拟年轻小鼠的这些代谢改变，可以显著加速小纤维神经病变的发生，同时减少脂肪。通过膳食补充丝氨酸的正常化和用肉豆蔻素缓解血脂异常都可以缓解糖尿病小鼠的神经病变，这将丝氨酸相关的周围神经病变与鞘脂代谢联系起来。这些发现确定了全身性丝氨酸缺乏和血脂异常是周围神经病变的新危险因素，并可以在治疗上加以利用。

据悉，糖尿病是一种代谢功能障碍损害多个器官系统的疾病，包括肝脏、肾脏和外周神经。虽然这些共病的发生和进展与胰岛素抵抗、高血糖和血脂异常有关，但异常的非必需氨基酸（NEAA）代谢也有助于糖尿病的发病。丝氨酸和甘氨酸是密切相关的NEAA，其水平在代谢综合征患者中持续降低，但这种代谢型的机制驱动因素和下游后果尚不清楚。低系统性丝氨酸和甘氨酸也出现为黄斑和周围神经疾病的标志，与视力受损和周围神经病变相关。

附：英文原文

Title: Insulin-regulated serine and lipid metabolism drive peripheral neuropathy

Author: Handzlik, Michal K., Gengatharan, Jivani M., Frizzi, Katie E., McGregor, Grace H., Martino, Cameron, Rahman, Gibraan, Gonzalez, Antonio, Moreno, Ana M., Green, Courtney R., Guernsey, Lucie S., Lin, Terry, Tseng, Patrick, Ideguchi, Yoichiro, Fallon, Regis J., Chaix, Amandine, Panda, Satchidananda, Mali, Prashant, Wallace, Martina, Knight, Rob, Gantner, Marin L., Calcutt, Nigel A., Metallo, Christian M.

Issue&Volume: 2023-01-25

Abstract: Diabetes represents a spectrum of disease in which metabolic dysfunction damages multiple organ systems including liver, kidneys and peripheral nerves1,2. Although the onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidaemia3,4,5,6,7, aberrant non-essential amino acid (NEAA) metabolism also contributes to the pathogenesis of diabetes8,9,10. Serine and glycine are closely related NEAAs whose levels are consistently reduced in patients with metabolic syndrome10,11,12,13,14, but the mechanistic drivers and downstream consequences of this metabotype remain unclear. Low systemic serine and glycine are also emerging as a hallmark of macular and peripheral nerve disorders, correlating with impaired visual acuity and peripheral neuropathy15,16. Here we demonstrate that aberrant serine homeostasis drives serine and glycine deficiencies in diabetic mice, which can be diagnosed with a serine tolerance test that quantifies serine uptake and disposal. Mimicking these metabolic alterations in young mice by dietary serine or glycine restriction together with high fat intake markedly accelerates the onset of small fibre neuropathy while reducing adiposity. Normalization of serine by dietary supplementation and mitigation of dyslipidaemia with myriocin both alleviate neuropathy in diabetic mice, linking serine-associated peripheral neuropathy to sphingolipid metabolism. These findings identify systemic serine deficiency and dyslipidaemia as novel risk factors for peripheral neuropathy that may be exploited therapeutically.

DOI: 10.1038/s41586-022-05637-6

Source: https://www.nature.com/articles/s41586-022-05637-6

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