Does Variation in Mean Red Cell Age Impact HbA1c Interpretation?

描述（由申请人提供）： 糖尿病退伍军人并发症的预防在很大程度上取决于血糖和HbA1c的评估，HbA1c是一种衡量血红蛋白（Hb）在红细胞（RBC）寿命期间暴露于平均血糖的指标，是最依赖的血糖控制指标。然而，HbA1c解释中的一个关键假设，即糖尿病患者和正常红细胞（RBC）的红细胞（RBC）存活范围很窄，最近已被证明是无效的。使用更精确的生物素标记方法表明，在其他正常人群中，RBC存活率存在显著异质性。RBC存活率的变化足以使测量的HbA1c的血糖控制估计值改变多达30%，这引起了HbA1c值在大量患者中不意味着相同的问题。这将需要一种方法来评估何时以及如何修改HbA1c解释。尽管证据清楚地表明，人与人之间的RBC存活率存在差异，但将这种差异归因于个体之间的差异取决于回答几个简单的问题，这些问题令人惊讶地仍未得到回答：RBC存活率是否随时间推移而稳定在个体内，血糖控制是否影响其稳定性。因此，拟议研究的目标是定义这些特征。第一个特定目的检验了平均RBC年龄在无糖尿病受试者和血糖控制稳定的糖尿病受试者中稳定的假设。第二个特定目标检验了这样一个假设，即在最初血糖控制不佳的糖尿病受试者中，平均RBC年龄不会发生变化，并且在接受稳定、改善的血糖控制>8个月后再次发生变化。为了实现这两个目标，将在10例无糖尿病受试者、10例血糖控制稳定的糖尿病受试者和最多15例初始血糖控制不佳的糖尿病受试者中分两次测定RBC存活率和平均血糖，间隔至少4个月，以便对10例随后血糖控制改善的受试者进行再研究。将使用相同的新型生物素RBC标记结合通过连续葡萄糖监测测定平均葡萄糖来测量RBC存活。HbA1c是长期监测血糖控制的最有价值的临床测试，糖尿病并发症风险的预测是每年在糖尿病退伍军人中做出的数十万临床决策的基础。拟议的研究，通过进一步定义红细胞生存稳定性必要的发展一种新的方法来解释HbA1c，因此有可能大大支持退伍军人事务部的使命，以减少糖尿病及其并发症的负担。

DESCRIPTION (provided by applicant): Prevention of complications in veterans with diabetes depends heavily on assessment of blood glucose and HbA1c, a measure of the exposure of hemoglobin (Hb) to average blood glucose over the lifespan of a red blood cell (RBC), is the test most heavily relied upon as a glycemic control indicator. However, one of the key assumptions in HbA1c interpretation, namely that there is a narrow range of red blood cell (RBC) survival in people with diabetes and normal RBCs, has recently been shown to not be valid. Use of a more precise biotin label method demonstrates substantial heterogeneity of RBC survival among otherwise normal people. There is sufficient variation in RBC survival to alter the estimate of glycemic control from measured HbA1c by as much as 30% which introduces concern that HbA1c values do not mean the same thing in a significant number of patients. This will necessitate a means to assess when and how to modify HbA1c interpretation. Although the evidence is clear that there is variation in RBC survival among people, attributing this variation to differences between individuals depends on answering several simple questions which surprisingly remain unanswered: whether RBC survival is stable over time within an individual and whether blood glucose control affects its stability. Therefore, the goal of the proposed studies is to define these characteristics. The first Specific Aim tests the hypothesis that mean RBC age is stable in subjects without diabetes and in subjects with diabetes at stable glycemic control. The second Specific Aim tests the hypothesis that mean RBC age will not change in subjects with diabetes studied initially in poor glycemic control, and again after being treated to stable, improved glycemic control for >8 months. To accomplish the two aims, RBC survival and mean blood glucose will be determined at two times separated by at least four months in 10 subjects without diabetes, 10 subjects with diabetes and stable glycemic control, and up to 15 subjects with diabetes in initial poor glycemic control in order to re-study 10 subjects subsequently in improved glycemic control. The RBC survival will be measured using the same novel biotin RBC label in conjunction with mean glucose determination by continuous glucose monitoring. HbA1c is the most highly valued clinical test for long term monitoring of glycemic control and the prediction of diabetes complications risk is relied upon for hundreds of thousands of clinical decisions made every year in veterans with diabetes. The proposed studies, by further defining RBC survival stability necessary to develop a new approach to HbA1c interpretation, therefore has the potential to dramatically support the Department of Veterans Affairs in its mission to reduce the burden of diabetes and its complications.