The Glycosylation Gap and Diabetic Complications

描述（由申请人提供）： 血红蛋白A1 c（Hb 1c）是评估糖尿病控制的金标准，但有些患者的HbA 1c与血糖不一致。我们开发了一种测量Hb 1c和血糖控制的血浆测试之间不一致性的方法，即“糖基化间隙”（GG）。GG是高度可重复的，与一个重要的临床结果，糖尿病肾病，并出现遗传相关。HbA 1c和葡萄糖监测（Hb糖基化指数）之间的平行测量方差已被证明可预测DCCT中的视网膜病变和肾病。这些数据表明，HbA 1c（表示为GG）的变化是由生物学机制引起的，这些生物学机制以迄今为止尚未认识到的方式导致糖尿病并发症。由于HbA 1c由红细胞（RBC）葡萄糖浓度、Hb糖基化速率和RBC寿命决定，因此本提案检查了糖尿病和非糖尿病人群中这些因素的变异性。我们发现红细胞葡萄糖相对于细胞外葡萄糖有很大的变化。这种体外红细胞膜葡萄糖梯度（EMGG）与GG相关，由此推断并发症风险较高。红细胞和内皮细胞-糖尿病并发症发生的主要细胞类型-共享相同的葡萄糖转运蛋白GLUT 1，这一事实提出了一个问题，即这一发现是否是由两种组织中共享的GLUT 1变异介导的。这些研究将试图确定：（1）GLUT 1功能的变化是否有助于HbA 1c的变化;（2）RBC寿命或HbA 1c形成率的变化如何有助于HbA 1c的变化;（3）长期血糖控制如何影响EMG和GG，以及它们是否代表遗传研究的可重复表型。这些研究为理解HbA 1c变异的重要来源提供了一种全面的方法。在美国，EMG的变化可能占每年> 3000万HbA 1c测量值总变化的11%。该建议将对并发症风险的考虑从血浆中的葡萄糖浓度扩展到细胞内的葡萄糖浓度。因此，该提案具有潜在的重要基础科学，临床和人口影响。

DESCRIPTION (provided by applicant): Hemoglobin A1c (Hb1c) is the gold standard for assessing diabetes control yet some patients have HbA1c discordant from plasma glucose. We developed a measure of the discordance between Hb1c and a plasma test of glycemic control, the "Glycosylation Gap" (GG). The GG is highly reproducible, correlates with an important clinical outcome, diabetic nephropathy, and appears genetically linked. A parallel measure of variance between HbA1c and glucose monitoring (Hb glycosylation index), has been shown to predict retinopathy and nephropathy in the DCCT. These data suggest that variation in HbA1c, expressed as the GG, arises from biological mechanism(s) that contribute to diabetic complications in here-to-fore unrecognized ways. Since HbA1c is determined by red blood cell (RBC) glucose concentration, the rate of Hb glycosylation and RBC lifespan, this proposal examines the variability of these factors in diabetic and non-diabetic populations. We found substantial variation in RBC glucose relative to extracellular glucose. This in vitro erythrocyte membrane glucose gradient (EMGG) correlated with GG and by inference with a higher risk of complications. The fact that the RBC and the endothelial cell - the major cell type in which diabetic complications occur - share the same glucose transporter, GLUT1, raises the question whether this finding is mediated by shared GLUT1 variation in the two tissues. These studies will seek to determine: (1) whether variation in GLUT1 function contributes to variation in HbA1c; (2) how variation in RBC lifespan or HbA1c formation rate contributes to HbA1c variability; (3) how long-term glycemic control affects the EMGG and the GG, and whether they represent reproducible phenotypes for genetic studies. These studies provide a comprehensive approach to understanding important sources of variation in HbA1c. The variation in EMGG could account for 11% of total variation in >30 million HbA1c measurements yearly in the United States. This proposal extends the consideration of complications risk from the glucose concentration in the plasma to the glucose concentration inside the cell. The proposal therefore has potentially important basic science, clinical and population implications.