Red blood cells in prediabetes: Early alterations, progressive trajectories, and clinical potential.

Red blood cells are not passive oxygen carriers. In overt type 2 diabetes, they have been proposed as both victims and amplifiers of metabolic and vascular dysfunction. Whether these alterations begin earlier in the prediabetic state is only beginning to emerge. This is the first comprehensive mechanistic review to synthesize evidence on RBC dysfunction in prediabetes. We aim to answer three questions. First, what happens to RBCs in prediabetes? We synthesize evidence on altered redox status, membrane composition, morphology, rheology, RBC-indices and function. Second, do these changes follow a predictable pattern as glycemia worsens? Based on available evidence, we propose a hypothesis-generating conceptual framework of progressive, plateau, late, and non-linear (peak, trough, and biphasic) trajectories, that warrants systematic validation through prospective studies. Third, can RBC markers be clinically useful? We evaluate their diagnostic, therapeutic, and screening potential, and assess the confounders that may limit their clinical utility. In conclusion, RBCs in prediabetes and diabetes are not merely mirrors of glycemia but appear to be hubs where altered oxidative stress, metabolism, and vascular biology converge. However, realizing their clinical promise will require prospective studies that account for the biological complexity of the RBC.