Impaired Amino Acid and TCA Metabolism and Cardiovascular Autonomic Neuropathy Progression in Type 1 Diabetes
Impaired Amino Acid and TCA Metabolism and Cardiovascular Autonomic Neuropathy Progression in Type 1 Diabetes
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DOI：
10.2337/db19-0145
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发表时间：
2019-10-01
期刊：
影响因子：
7.7
通讯作者：
Pop-Busui, Rodica
中科院分区：
文献类型：
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作者：
Mathew, Anna, V;Jaiswal, Mamta;Pop-Busui, Rodica
虽然糖尿病以高血糖为特征，但氨基酸和三羧酸(TCA)循环等营养代谢途径也受到严重干扰。由于血糖控制本身不能预防并发症，我们假设这些代谢紊乱是糖尿病心血管自主神经病变(CAN)的发生和发展的原因。我们对1型糖尿病患者和健康对照组进行了标准化的心血管自主神经反射试验，并对其进行了3年的空腹血浆氨基酸和TCA循环中间产物代谢组学分析。与10名年龄匹配的健康受试者相比，47名1型糖尿病患者(女性占60%，年龄35+/-13年，糖尿病病程13+/-7年，糖化血红蛋白7.9+/-1.2%)富马酸水平较低，苏氨酸、丝氨酸、丙氨酸、天冬氨酸、天冬氨酸、苯丙氨酸、酪氨酸和组氨酸水平较高。较高的基线富马酸水平和较低的基线氨基酸水平-天冬酰胺和谷氨酰胺-与CAN(较低的正常R-R间期[SDNN]基线标准差)相关。在调整了基线HBA(1c)、血糖、体重指数、胆固醇、尿微量白蛋白/肌酐比值、估计肾小球滤过率和糖尿病年数后，基线谷氨酰胺和鸟氨酸水平分别与CAN的进展(3年后SDNN降低)和SDNN的变化相关。因此，进入TCA循环的逆性通量的显著变化可能是导致CAN进展的关键缺陷。
While diabetes is characterized by hyperglycemia, nutrient metabolic pathways like amino acid and tricarboxylic acid (TCA) cycle are also profoundly perturbed. As glycemic control alone does not prevent complications, we hypothesized that these metabolic disruptions are responsible for the development and progression of diabetic cardiovascular autonomic neuropathy (CAN). We performed standardized cardiovascular autonomic reflex tests and targeted fasting plasma metabolomic analysis of amino acids and TCA cycle intermediates in subjects with type 1 diabetes and healthy control subjects followed for 3 years. Forty-seven participants with type 1 diabetes (60% female and mean +/- SD age 35 +/- 13 years, diabetes duration 13 +/- 7 years, and HbA(1c) 7.9 +/- 1.2%) had lower fumarate levels and higher threonine, serine, proline, asparagine, aspartic acid, phenylalanine, tyrosine, and histidine levels compared with 10 age-matched healthy control subjects. Higher baseline fumarate levels and lower baseline amino acid levels-asparagine and glutamine-correlate with CAN (lower baseline SD of normal R-R interval [SDNN]). Baseline glutamine and ornithine levels also associated with the progression of CAN (lower SDNN at 3 years) and change in SDNN, respectively, after adjustment for baseline HbA(1c), blood glucose, BMI, cholesterol, urine microalbumin-to- creatinine ratio, estimated glomerular filtration rate, and years of diabetes. Therefore, significant changes in the anaplerotic flux into the TCA cycle could be the critical defect underlying CAN progression.