Glycated Hemoglobin, Plasma Glucose, and Erythrocyte Aging

Abstract

Background: The relationship between HbA1c and blood glucose averages has been characterized many times, yet, a unifying, mechanistic description is still lacking.

Methods: We calculated the level of HbA1c from plasma glucose averages based solely on the in vivo rate of hemoglobin glycation, and the different turnover rates for erythrocytes of different ages. These calculations were then compared to the measured change of HbA1c due to changes in mean blood glucose (MBG), to complex models in the literature, and our own experiments.

Results: Analysis of data on erythrocyte ageing patterns revealed that 2 separate RBC turnover mechanisms seem to be present. We calculated the mean red blood cell (RBC) life span within individuals to lie between 60 and 95 days. Comparison of expected HbA1c levels to data taken from continuous glucose monitors and finger-stick MBG yielded good agreement (r = .87, P < .0001). Experiments on the change with time of HbA1c induced by a change of MBG were in excellent agreement with our calculations (r = .98, P < .0001).

Conclusions: RBC turnover seems to be dominated by a constant rate of cell loss, and a mechanism that targets cells of a specific age. Average RBC life span is 80 ± 10.9 days. Of HbA1c change toward treatment goal value, 50% is reached in about 30 days. Many factors contribute to the ratio of glycated hemoglobin, yet we can make accurate estimations considering only the in vivo glycation constant, MBG, and the age distribution of erythrocytes.

Keywords: blood sugar control; continuous glucose monitor; erythrocyte life span; glycated hemoglobin.

Figure 1.

Example of biotinylated RBC survival curve (data from Cohen et al). Diamonds are biotynilated RBC survival ratios. The following fits are shown: a constrained quadratic ($f\left(t\right)=a{t}^2+bt+1$R² = .998, solid line), linear (homogeneous life-span model, R² = .979, dot-dashed line), and exponential (random death model, R² = .976, dashed line).

Figure 2.

Calculated and experimental values of HbA1c % vs MBG (chronic pancreatitis patients from Beltrán del Río et al, circles; Healthy volunteers from Beltrán del Río et al, diamonds; diabetes mellitus from Kovatchev et al, dots; diabetes mellitus from Nathan et al, crosses; diabetes mellitus from Nathan et al, squares). The 3 predictions correspond to different values of erythrocyte life spans: MEL = 117d, solid line; MEL = 140d, dashed line; MEL = 97d, dot-dashed line. The inset shows the correlation between experimental and expected HbA1c values (MEL = 117d) of all combined data (dots in inset).

Figure 3.

Rate for change of HbA1c % after a stepwise change in MBG. The 3 estimates correspond to calculations based on different erythrocyte life spans: MEL = 117d, solid line; MEL = 140d, dashed line; MEL = 97d, dot-dashed line. Data in diamonds are measurements from Tahara and Shima.