HbA1c reconsidered: glycated haemoglobin in the era of dynamic erythrocyte glucose metabolism

Abstract Glycated haemoglobin (HbA1c) has been the standard biomarker of long-term glycaemic control for four decades. It rests on a tacit assumption: that non-enzymatic haemoglobin glycation is governed chiefly by mean plasma glucose, with erythrocyte intracellular glucose in passive equilibrium with plasma. This requires erythrocyte glucose uptake—and thus glucose transporter 1 (GLUT1) expression—to be effectively constant. The 2026 demonstration that chronic hypoxia upregulates erythrocyte GLUT1 approximately twofold and per-cell glucose uptake approximately threefold, together with evidence that the band 3 N-terminus acts as a bidirectional metabolic switch responsive to haemoglobin oxygenation, challenges this assumption. We propose that HbA1c is better understood as integrating erythrocyte intracellular glucose exposure, a quantity predicted to diverge from plasma glucose when the erythrocyte oxygen environment or red cell turnover is altered. We review reported discordance in high-altitude populations, obstructive sleep apnoea, cyanotic congenital heart disease, critical illness and chronic kidney disease, and propose testable predictions and a research roadmap. The framework is intended to complement, not replace, established explanations such as altered red cell survival, erythropoiesis, iron status and analytical interference. No human study has yet measured erythrocyte GLUT1 expression, intracellular glucose exposure and HbA1c discordance concurrently; the framework is therefore presented as a hypothesis for prospective testing rather than as a basis for changing clinical practice.