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Evidence for Interindividual Heterogeneity in the Glucose Gradient Across the Human Red Blood Cell Membrane and Its Relationship to Hemoglobin Glycation

¹ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio
² Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, Ohio
³ Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts
⁴ Division of Emergency Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio
⁵ Division of Hematology and Oncology, Department of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio
⁶ Medical Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio

Corresponding author: Robert M. Cohen, robert.cohen{at}uc.edu

OBJECTIVE—To determine whether interindividual heterogeneity in the erythrocyte (red blood cell [RBC]) transmembrane glucose gradient might explain discordances between A1C and glycemic control based on measured fructosamine.

RESEARCH DESIGN AND METHODS—We modeled the relationship between plasma glucose and RBC glucose as the concentration distribution (C_i-to-C_o ratio) of a nonmetabolizable 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 hemoglobin in comparison with glycation of serum proteins (fructosamine), the glycation gap. A1C, fructosamine, and in vitro determination of the ¹⁴C-3OMG distribution in glucose-depleted RBCs were measured in 26 fasted subjects.

RESULTS—The C_i-to-C_o ratio 0.89 ± 0.07 for 3-O-methyl-D-glucopyranose (3OMG) ranged widely (0.72–1.04, n = 26). In contrast, urea C_i-to-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-to-C_o ratio was retained in RBC ghosts, was not dependent on ATP or external cations, and was reestablished after reversal of the glucose gradient. The 3OMG C_i-to-C_o ratio was not correlated with serum fructosamine, suggesting that it was independent of mean plasma glucose. However, C_i-to-C_o did correlate with A1C (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 A1C for given level of glycemic control.

CONCLUSIONS—The data demonstrate interindividual heterogeneity in glucose gradients across RBC membranes that may affect hemoglobin glycation and have implications for diabetes complications risk and risk assessment.

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