Bakillah Ahmed, Soliman Ayman Farouk, Al Subaiee Maram, Obeid Khamis Khamees, Al Hussaini Arwa, Bashir Shahinaz Faisal, Al Arab Mohammad, Al Otaibi Abeer, Mubarak Sindiyan Al Shaikh, Al Qarni Ali Ahmed
King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 31982, Saudi Arabia.
Division of Biomedical Research Core Facility, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia.
Int J Mol Sci. 2025 Mar 25;26(7):3001. doi: 10.3390/ijms26073001.
In individuals with type 2 diabetes mellitus (T2DM), elevated levels of both plasma and urinary cystatin C (Cys-C) contribute to increased oxidation, which in turn accelerates the oxidation of low-density lipoprotein (LDL). This process may worsen the development of atherosclerosis and cardiovascular disease by promoting endothelial dysfunction and inflammation. Despite its potential significance, the relationship between Cys-C and oxidized LDL (ox-LDL) in T2DM remains poorly understood. This study investigated the relationship between plasma and urinary Cys-C and ox-LDL levels in T2DM patients. The cohort included 57 patients with T2DM (mean age 61.14 ± 9.99 years; HbA1c 8.66 ± 1.60% and BMI 35.15 ± 6.65 kg/m). Notably, 95% of the patients had hypertension, 82% had dyslipidemia, 59% had an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m, 14% had coronary artery disease (CAD), and 5% had a history of stroke. Plasma and urinary Cys-C and ox-LDL levels were measured using ELISA. Adipokine and cytokine levels were measured using the multiplex MAP Human Adipokine Magnetic Bead Panels. Spearman's correlation analysis revealed a significant positive correlation of plasma and urinary Cys-C with ox-LDL (r = 0.569, = 0.0001 and r = 0.485, = 0.0001, respectively). Multivariable regression analysis indicated that both plasma and urinary Cys-C were independently associated with ox-LDL, after adjusting for confounding factors (β = 0.057, = 0.0001 and β = 0.486, = 0.003, respectively). Stepwise linear regression identified TNFα and adiponectin as the strongest predictors of the relationship between urinary Cys-C and ox-LDL (β = 0.382, = 0.0001; r = 0.64), while adiponectin alone was the best predictor of the plasma Cys-C and ox-LDL association (β = 0.051, = 0.005; r = 0.46). Furthermore, adiponectin partly mediated the relationship between plasma Cys-C and ox-LDL, explaining 18% of the variance in this association. In contrast, TNFα partly mediated the relationship between urinary Cys-C and ox-LDL, accounting for 28% of the variance. This study emphasizes the complex interaction between Cys-C and ox-LDL in T2DM. It highlights the need for additional research involving larger patient cohorts to improve our understanding of the therapeutic potential of plasma and urinary Cys-C in conjunction with ox-LDL for managing complications associated with T2DM.
在2型糖尿病（T2DM）患者中，血浆和尿胱抑素C（Cys-C）水平升高会导致氧化增加，进而加速低密度脂蛋白（LDL）的氧化。这一过程可能通过促进内皮功能障碍和炎症，使动脉粥样硬化和心血管疾病的发展恶化。尽管其具有潜在意义，但T2DM中Cys-C与氧化型LDL（ox-LDL）之间的关系仍知之甚少。本研究调查了T2DM患者血浆和尿Cys-C与ox-LDL水平之间的关系。该队列包括57例T2DM患者（平均年龄61.14±9.99岁；糖化血红蛋白8.66±1.60%，体重指数35.15±6.65kg/m）。值得注意的是，95%的患者患有高血压，82%患有血脂异常，59%的估计肾小球滤过率（eGFR）<60mL/min/1.73m²，14%患有冠状动脉疾病（CAD），5%有中风病史。采用酶联免疫吸附测定法（ELISA）测量血浆和尿Cys-C以及ox-LDL水平。使用多重MAP人脂肪因子磁珠板测量脂肪因子和细胞因子水平。Spearman相关性分析显示，血浆和尿Cys-C与ox-LDL呈显著正相关（r分别为0.569，P = 0.0001和r = 0.485，P = 0.0001）。多变量回归分析表明，在调整混杂因素后，血浆和尿Cys-C均与ox-LDL独立相关（β分别为0.057，P = 0.0001和β = 0.486，P = 0.003）。逐步线性回归确定肿瘤坏死因子α（TNFα）和脂联素是尿Cys-C与ox-LDL关系的最强预测因子（β = 0.382，P = 0.0001；r = 0.64），而单独的脂联素是血浆Cys-C与ox-LDL关联的最佳预测因子（β = 0.051，P = 0.005；r = 0.46）。此外，脂联素部分介导了血浆Cys-C与ox-LDL之间的关系，解释了该关联中18%的变异。相比之下，TNFα部分介导了尿Cys-C与ox-LDL之间的关系，占变异的28%。本研究强调了T2DM中Cys-C与ox-LDL之间复杂的相互作用。它突出了需要开展涉及更大患者队列的进一步研究，以增进我们对血浆和尿Cys-C联合ox-LDL在管理T2DM相关并发症方面治疗潜力的理解。
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