Hypoglycemia limits endurance performance without carbohydrate ingestion, but what limits it when blood glucose is maintained via periodic carbohydrate ingestion?

The mechanisms underlying fatigue during prolonged exercise remain a topic of ongoing debate. A recent review by Noakes et al. proposes that exercise-induced hypoglycemia (EIH), rather than skeletal muscle glycogen depletion, is a primary determinant of exercise termination, and that prolonged exercise is interrupted by centrally mediated protective mechanism to ensure that fatal neuroglycopenia does not develop. By reanalyzing studies reporting blood glucose at exhaustion, we highlight that, in the absence of carbohydrate (CHO) ingestion, exercise termination consistently coincides with clinically relevant hypoglycemia, supporting the suggestion that low levels of blood glucose operate as an important afferent signal to the brain. However, when CHO is periodically ingested during exercise, exercise termination occurs despite the maintenance of blood glucose within near-resting levels. Thus, blood glucose concentration may no longer represent the dominant afferent signal contributing to exercise termination when CHO is ingested. Instead, other physiological constraints, such as thermal and cardiovascular strain and peripheral muscle perturbations may become increasingly relevant as exercise is prolonged by CHO ingestion. A deeper understanding of how multiple afferent signals interact to regulate muscle recruitment during prolonged exercise may provide new insights for both exercise physiology and sports nutrition. While the recent review of Noakes et al. represents a major advancement toward redefining the role of blood glucose in exercise capacity, it also opens a compelling avenue for future research to clarify the primary limiting factors when prolonged exercise is terminated in the absence of hypoglycemia.