Vaishnav Madhumati S, Kumari Namita, Srikanta Sathyanarayana, Simha Vinaya, Krishnaswamy Patnam R, Balaram Padmanabhan, Bhat Navakanta
Centre for Nano Science and Engineering, Indian Institute of Science, Bengaluru, India.
Samatvam Endocrinology Diabetes Center, Jnana Sanjeevini Diabetes Hospital and Medical Center, Bengaluru, India.
Metab Syndr Relat Disord. 2024 Jun;22(5):372-384. doi: 10.1089/met.2023.0275. Epub 2024 May 2.
Cys34 albumin redox modifications (reversible "cysteinylation" and irreversible "di/trioxidation"), besides being just oxidative stress biomarkers, may have primary pathogenetic roles to initiate and/or aggravate cell, tissue, and vascular damage in diabetes. In an exploratory "proof-of-concept" pilot study, we examined longitudinal changes in albumin oxidation during diabetes therapy. Mass spectrometric analysis was utilized to monitor changes in human serum albumin (HSA) post-translational modifications {glycation [glycated albumin (GA)], cysteinylation [cysteinylated albumin (CA) or human non-mercaptalbumin-1; reversible], di/trioxidation (di/trioxidized albumin or human non-mercaptalbumin-2; irreversible), and truncation (truncated albumin)} during ongoing therapy. Four informative groups of subjects were evaluated [type 1 diabetes (T1DM), type 2 diabetes (T2DM), prediabetes-obesity, and healthy controls] at baseline, and subjects with diabetes were followed for a period up to 280 days. At baseline, T2DM was associated with relatively enhanced albumin cysteinylation (CA% total) compared with T1DM ( = 0.004), despite comparable mean hyperglycemia ( values: hemoglobin A1c = 0.09; GA = 0.09). T2DM, compared with T1DM, exhibited selectively and significantly higher elevations of all the "individual" glycated cum cysteinylated ("multimodified") albumin isoforms ( values: CysHSA+1G = 0.003; CysHSA+2G = 0.007; and CysHSA+3G = 0.001). Improvements in glycemic control and decreases in albumin glycation during diabetes therapy in T2DM were not always associated with concurrent reductions of albumin cysteinylation, and in some therapeutic situations, albumin cysteinylation worsened (glycation-cysteinylation discordance). Important differences were observed between the effects of sulfonylureas and metformin on albumin molecular modifications. T2DM was associated with higher oxidative (cysteinylation) and combined (cysteinylation plus glycation) albumin molecular modifications, which are not ameliorated by improved glucose control alone. Further studies are required to establish the clinical significance and optimal therapeutic strategies to address oxidative protein damage and resulting consequences in diabetes.
半胱氨酸34位白蛋白的氧化还原修饰（可逆的“半胱氨酸化”和不可逆的“二/三氧化”），除了作为氧化应激生物标志物外，可能在糖尿病中引发和/或加重细胞、组织和血管损伤方面具有原发性致病作用。在一项探索性的“概念验证”试点研究中，我们研究了糖尿病治疗期间白蛋白氧化的纵向变化。利用质谱分析来监测在持续治疗期间人血清白蛋白（HSA）的翻译后修饰变化{糖基化[糖化白蛋白（GA）]、半胱氨酸化[半胱氨酸化白蛋白（CA）或人非巯基白蛋白-1；可逆]、二/三氧化（二/三氧化白蛋白或人非巯基白蛋白-2；不可逆）和截短（截短白蛋白）}。在基线时评估了四组信息丰富的受试者[1型糖尿病（T1DM）、2型糖尿病（T2DM）、糖尿病前期肥胖和健康对照]，并且对糖尿病患者随访了长达280天的时间。在基线时，尽管平均高血糖水平相当（数值：糖化血红蛋白A1c = 0.09；GA = 0.09），但与T1DM相比，T2DM与相对增强的白蛋白半胱氨酸化（CA占总量的百分比）相关（P = 0.004）。与T1DM相比，T2DM表现出所有“单个”糖化累积半胱氨酸化（“多修饰”）白蛋白异构体有选择性且显著更高的升高（数值：CysHSA + 1G = 0.003；CysHSA + 2G = 0.007；CysHSA + 3G = 0.001）。在T2DM的糖尿病治疗期间，血糖控制的改善和白蛋白糖基化的降低并不总是与白蛋白半胱氨酸化的同时降低相关，并且在某些治疗情况下，白蛋白半胱氨酸化会恶化（糖基化 - 半胱氨酸化不一致）。观察到磺脲类药物和二甲双胍对白蛋白分子修饰的影响存在重要差异。T2DM与更高的氧化（半胱氨酸化）和联合（半胱氨酸化加糖化）白蛋白分子修饰相关，仅改善血糖控制并不能改善这些修饰。需要进一步研究以确定解决糖尿病中氧化蛋白损伤及其后果的临床意义和最佳治疗策略。
