Molecular Biomarkers, The Biodesign Institute at Arizona State University, Tempe, AZ, USA.
Clin Chem. 2011 May;57(5):719-28. doi: 10.1373/clinchem.2010.156976. Epub 2011 Mar 14.
In 2008, the US Food and Drug Administration (FDA) issued a Guidance for Industry statement formally recognizing (during drug development) the conjoined nature of type 2 diabetes (T2D) and cardiovascular disease (CVD), which has precipitated an urgent need for panels of markers (and means of analysis) that are able to differentiate subtypes of CVD in the context of T2D. Here, we explore the possibility of creating such panels using the working hypothesis that proteins, in addition to carrying time-cumulative marks of hyperglycemia (e.g., protein glycation in the form of Hb A(₁c)), may carry analogous information with regard to systemic oxidative stress and aberrant enzymatic signaling related to underlying pathobiologies involved in T2D and/or CVD.
We used mass spectrometric immunoassay to quantify, in targeted fashion, relative differences in the glycation, oxidation, and truncation of 11 specific proteins.
Protein oxidation and truncation (owing to modified enzymatic activity) are able to distinguish between subsets of diabetic patients with or without a history of myocardial infarction and/or congestive heart failure where markers of glycation alone cannot.
Markers based on protein modifications aligned with the known pathobiologies of T2D represent a reservoir of potential cardiovascular markers that are needed to develop the next generation of antidiabetes medications.
2008 年，美国食品和药物管理局（FDA）发布了一份行业指南，正式承认（在药物开发过程中）2 型糖尿病（T2D）和心血管疾病（CVD）的联合性质，这促使人们迫切需要能够在 T2D 背景下区分 CVD 亚型的标志物（和分析手段）。在这里，我们探索了使用工作假设创建此类面板的可能性，该假设认为蛋白质除了携带高血糖的时间累积标记（例如 Hb A₁c 形式的蛋白质糖化）之外，还可能携带与系统性氧化应激和与 T2D 和/或 CVD 相关的潜在病理生物学有关的异常酶信号有关的类似信息。
我们使用质谱免疫测定法以靶向方式定量 11 种特定蛋白质的糖化、氧化和截断的相对差异。
蛋白质氧化和截断（由于酶活性改变）能够区分有或没有心肌梗死和/或充血性心力衰竭病史的糖尿病患者亚组，而仅用糖化标志物则无法区分。
与 T2D 的已知病理生物学相一致的基于蛋白质修饰的标志物代表了潜在心血管标志物的储备，这些标志物是开发下一代抗糖尿病药物所必需的。
