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. PUBLIC HEALTH RELEVANCE: Prevention of complications of diabetes depends heavily on the assessment of blood glucose control which in turn depends on interpretation of HbA1c results. Our laboratory has demonstrated that one of the key assumptions in HbA1c interpretation, that there is a narrow range of red blood cell (RBC) survival in people with diabetes and normal RBCs, is not valid: Rather the heterogeneity of RBC survival among otherwise normal people can introduce dramatic differences in HbA1c sufficient to alter clinical decisions. The proposed studies are directed toward understanding the stability of RBC survival, a key determinant of HbA1c, and whether RBC survival is a source of variation in the dependence of HbA1c on mean blood glucose which in turn underlies hundreds of thousands of clinical decisions made every year in veterans with diabetes.