Evidence for inter-individual heterogeneity in the glucose gradient across the human RBC membrane and its relationship to hemoglobin glycation

Abstract

Objective: To determine whether inter-individual heterogeneity in the erythrocyte (RBC) transmembrane glucose gradient might explain discordances between HbA1c and glycemic control based on measured fructosamine (FA).

Research Design and Methods: We modeled the relationship between plasma glucose and RBC glucose as the concentration distribution (C_i/C_o ratio) of a non-metabolizable glucose analog ¹⁴C-3-O-methyl glucose (¹⁴C-3OMG) inside (C_i) and outside (C_o) RBCs in vitro. We examined the relationship between that distribution and the degree of glycation of Hb in comparison to glycation of serum proteins (FA), the glycation gap. HbA1c, FA and in vitro determination of the ¹⁴C-3OMG distribution in glucose-depleted RBCs were measured fasting on 26 subjects.

Results: The C_i/C_o ratio 0.89±0.07 (mean±SD) for 3OMG ranged widely (0.72-1.04, n=26). In contrast, urea C_i/C_o (1.015±0.022; range 0.98-1.07; P<0.0001) did not. Concerning mechanism, in a representative subset of subjects, the C_i/C_o ratio was retained in RBC ghosts, was not dependent on ATP or external cations, and was re-established after reversal of the glucose gradient. The 3OMG C_i/C_o ratio was not correlated with serum FA, suggesting that it was independent of mean plasma glucose. However, C_i/C_o did correlate with HbA1c (R²=0.19) and with the glycation gap (R²=0.20), consistent with a model in which differences in internal glucose concentration at a given mean plasma glucose contribute to differences in HbA1c for given level of glycemic control.

Conclusions: The data demonstrate inter-individual heterogeneity in glucose gradients across RBC membranes which may affect Hb glycation and have implications for diabetes complications risk and risk assessment.