A Kinetic Model for Glucose Levels and Hemoglobin A1c Provides a Novel Tool for Individualized Diabetes Management

Background: Regular assessment of glycated hemoglobin (HbA1c) is central to the management of patients with diabetes. Estimated HbA1c (eHbA1c) from continuous glucose monitoring (CGM) has been proposed as a measure that reflects laboratory HbA1c. However, discrepancies between the two markers are common, limiting the clinical use of eHbA1c. Therefore, developing a glycemic maker that better reflects laboratory HbA1c will be highly relevant in diabetes management. Methods: Using CGM data from two previous clinical studies in 120 individuals with diabetes, we derived a novel kinetic model that takes into account red blood cell (RBC) turnover, cross-membrane glucose transport, and hemoglobin glycation processes to individualize the relationship between glucose levels and HbA1c. Results: Using CGM data and two laboratory HbA1c measurements, kinetic rate constants for RBC glycation and turnover were calculated. These rate constants were used to project future HbA1c, creating a new individualized glycemic marker, termed calculated HbA1c (cHbA1c). In contrast to eHbA1c, the new glycemic marker cHbA1c gave an accurate estimation of laboratory HbA1c across individuals. The model and data demonstrated a non-linear relationship between laboratory HbA1c and steady-state glucose and also showed that glycation status is modulated by age. Conclusion: Our kinetic model offers mechanistic insights into the relationship between glucose levels and glycated hemoglobin. Therefore, the new glycemic marker does not only accurately reflect laboratory HbA1c but also provides novel concepts to explain the mechanisms for the mismatch between HbA1c and average glucose in some individuals, which has implications for future clinical management.