Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
Nature. 2023 Feb;614(7946):118-124. doi: 10.1038/s41586-022-05637-6. Epub 2023 Jan 25.
Diabetes represents a spectrum of disease in which metabolic dysfunction damages multiple organ systems including liver, kidneys and peripheral nerves. Although the onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidaemia, aberrant non-essential amino acid (NEAA) metabolism also contributes to the pathogenesis of diabetes. Serine and glycine are closely related NEAAs whose levels are consistently reduced in patients with metabolic syndrome, 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 neuropathy. 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.
糖尿病代表了一种代谢功能障碍损害多个器官系统（包括肝脏、肾脏和外周神经）的疾病谱。尽管这些合并症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机制。丝氨酸和甘氨酸是密切相关的非必需氨基酸，代谢综合征患者的水平持续降低，但这种代谢类型的机制驱动因素和下游后果仍不清楚。低系统性丝氨酸和甘氨酸也成为黄斑和周围神经病变的标志，与视力障碍和周围神经病变相关。在这里，我们证明了异常的丝氨酸稳态导致糖尿病小鼠中的丝氨酸和甘氨酸缺乏，这可以通过丝氨酸耐量试验来诊断，该试验可以定量丝氨酸的摄取和处理。通过饮食限制丝氨酸或甘氨酸和高脂肪摄入来模拟这些代谢改变，再加上年轻小鼠中同时发生的这些改变，会显著加速小纤维神经病变的发生，同时减少肥胖。通过饮食补充使丝氨酸正常化和用米曲霉素减轻血脂异常，都能缓解糖尿病小鼠的神经病变，将与丝氨酸相关的周围神经病变与鞘脂代谢联系起来。这些发现确定了系统性丝氨酸缺乏和血脂异常是周围神经病变的新的危险因素，这可能在治疗上得到利用。
