“Glucose and A1C are among the most important biomarkers for diabetes management, with A1C generally believed to reflect a patient’s average glucose in the past 3 months,” explains Yongjin Xu, PhD. “However, differences between A1C and mean glucose are frequently observed in clinical practice. Recent research indicates that clinicians need be to be aware that A1C may not as accurately reflect mean glucose as previously thought. Therefore, the need exists to understand the factors involved to help align these measures, since they are so central to diabetes management decisions.”

To address this issue, Dr. Xu and colleagues analyzed continuous glucose monitoring (CGM) data from two previous clinical studies in 120 individuals with diabetes and published their findings in the Journal of Diabetes Science and Technology. The researchers derived a novel kinetic model that considers red blood cell (RBC) turnover, cross-membrane glucose transport, and hemoglobin glycation processes to individualize the relationship between glucose levels and A1C.

Two RBC Factors that Affect A1C

“Our model includes two factors related to RBCs that affect A1C,” Dr. Xu notes. “The first factor is RBC turnover, the rate at which RBCs are renewed by the body, which is approximately 1% per day. This process refreshes RBCs, and therefore, removes glycated hemoglobin, so variations like increasing turnover by 5% or 10% can affect A1C independently of mean blood glucose. However, RBC turnover can vary from person to person, which contributes to the glucose-A1C discordance issue.”  The second factor, Dr. Xu explains, is overall hemoglobin glycation, the process of glucose moving from the blood plasma into the RBC and chemically reacting with hemoglobin (Figure).

“We believe the RBC glucose uptake and hemoglobin glycation process can vary, most dominantly from the variation in glucose uptake rate, or GLUT1 level, on RBC,” says Dr. Xu. “With the model, we can estimate these personal parameters from high-quality CGM data paired in time with A1C measurements. Once the personal parameters are determined, we can use these to accurately project future A1C estimates derived from CGM data.”

Better Diabetes Management Decisions

There are known limitations to A1C measurements, particularly for people with conditions with which the measurement does not accurately reflect glucose exposure, Dr. Xu explains. “These are conditions that affect a person’s RBC turnover or RBC lifespan,” he adds. “Our model provides a quantitative formula to make an individual adjustment to A1C for a respective RBC lifespan. Additionally, it supports an accurate estimation of RBC lifespan by considering RBC glucose uptake and lifespan in the glucose-A1C relationship. The accuracy of our model is shown to be better than that of the routine approach of estimated A1C. By using a CGM system, a clinician can retrieve a patient’s complete glycemic picture and review it along with their A1C. These, combined with the understanding of personal RBC variations, can result in better diabetes management decisions.”

Dr. Xu and colleagues believe their findings are an important step in understanding how a patient’s blood glucose is reflected in A1C. “While there is guidance on conditions that affect A1C, some alterations in RBC turnover and glucose uptake may not be obvious in some patients and may need to be considered on an individual basis when evaluating A1C and glucose levels,” says Dr. Xu. “The new glycemic marker not only accurately reflects laboratory A1C, it also provides novel concepts to help explain the mechanisms for the mismatch between A1C and average glucose in some patients, which has implications for future clinical management.”

The study team agrees on the remaining, important need to confirm the variation in these RBC factors and further understand how they vary across groups of people with similar characteristics (age, disease duration, racial and ethnic background, and gender).  “Furthermore, more research is needed to associate these RBC factors with clinical outcomes, specifically on the individual level,” says Dr. Xu.