The Glycosylation Gap and Diabetic Complications

描述(由申请人提供)： 血红蛋白A1c(Hb1c)是评估糖尿病控制的金标准，但一些患者的HbA1c与血糖不一致。我们开发了一种测量Hb1c和血糖控制的血浆试验--“糖基化间隙”(GG)--之间不一致性的方法。GG具有很高的重复性，与一种重要的临床结局--糖尿病肾病相关，并且似乎与基因有关。HbA1c和血糖监测(Hb糖化指数)之间的平行差异测量已被证明可以预测DCCT中的视网膜病变和肾病。这些数据表明，糖化血红蛋白的变异(表示为GG)源于生物机制(S)，这种机制以迄今未被认识的方式导致糖尿病并发症。由于HbA1c是由红细胞(RBC)葡萄糖浓度、Hb糖化速率和RBC寿命决定的，因此该建议研究了这些因素在糖尿病和非糖尿病人群中的变异性。我们发现RBC葡萄糖相对于细胞外葡萄糖有很大的差异。这种体外红细胞膜葡萄糖梯度(EMGG)与GG相关，由此推断，发生并发症的风险更高。事实上，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GLUT1，这一事实引发了这样一个问题：这一发现是否由这两个组织中共同的GLUT1变异所介导。这些研究将试图确定：(1)GLUT1功能的变化是否导致HbA1c的变化；(2)RBC寿命或HbA1c形成率的变化如何影响HbA1c的可变性；(3)长期的血糖控制如何影响EMGG和GG，以及它们是否代表遗传学研究的可重复表型。这些研究为了解HbA1c的重要变异来源提供了一种全面的方法。肌电变化可能占美国每年3000万HbA1c测量总变化的11%。这项建议将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，这项提议可能具有重要的基础科学、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.