Is the glucose ketone index a biomarker of metabolic flexibility?

In their recent Frontiers in Science lead article, Lee et al. propose the glucose ketone index (GKI), the ratio of circulating glucose to β-hydroxybutyrate (BHB), as a quantitative biomarker for monitoring nutritional ketosis and supporting the prevention and management of cancer and chronic diseases (Lee et al., 2026). Their central argument is that mitochondrial dysfunction underlies most chronic disease, and that the balance between these two fuels offers a practical, point-of-care readout of metabolic status. We suggest these implications extend even further. Rather than serving solely as a measure of nutritional ketosis, the GKI may function as an integrated biomarker of metabolic flexibility: the body's capacity to transition efficiently between two evolutionarily conserved fuel systems as physiological demands change.Humans evolved to use both glucose-and fat-derived fuels according to nutrient availability.During feeding, glucose serves as an efficient energy source for tissues with obligate glucose requirements. During fasting, prolonged exercise, illness, or carbohydrate restriction, fatty acid oxidation increases and the liver produces ketone bodies that provide an alternative fuel for the brain, heart, skeletal muscle, and other tissues (Puchalska and Crawford, 2017). These pathways function cooperatively, allowing continuous adaptation to changing nutrient availability.In modern societies, however, frequent consumption of refined, carbohydrate-rich foods, chronic positive energy balance, and reduced physical activity have diminished the need to transition between glucose and fat metabolism. In particular, ingestion of refined sugar, high fructose corn syrup, and high glycemic carbohydrates has been proposed to activate a "fat switch," a conserved survival response that stimulates food intake, insulin resistance, and fat accumulation (Johnson et al., 2026). Chronic nutrient excess, particularly prolonged exposure to fructose, glucose, and insulin, promotes substrate overload, ectopic lipid accumulation, mitochondrial dysfunction, oxidative stress, and impaired insulin signaling. Metabolic flexibility declines as the ability to appropriately transition between carbohydrate and lipid metabolism is progressively lost, contributing to obesity, type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD), chronic kidney disease (CKD), and cardiovascular disease (Johnson et al., 2026;Petersen and Shulman, 2018;Galgani et al., 2008;Zeevi et al., 2015). These observations support the concept that metabolic dysfunction is driven not by a single nutrient but by the chronic mismatch between nutrient availability and the body's capacity to appropriately regulate substrate utilization (Johnson et al., 2026).Most clinical biomarkers quantify individual physiological processes rather than the dynamic relationship between glucose and fat metabolism. HbA1c integrates chronic glycemia, fasting insulin reflects basal insulin secretion, and continuous glucose monitoring (CGM) enables continuous assessment of glycemia. In this context, the GKI may represent the next evolution in metabolic monitoring, capturing the dynamic relationship between glucose and ketone metabolism and providing an integrated assessment of metabolic adaptation across nutritional, lifestyle, and pharmacologic interventions.This distinction is clinically important because glucose concentrations may improve through mechanisms that do not necessarily restore metabolic health. Pharmacologic glucose lowering, for example, can normalize glycemia without substantially improving insulin resistance or metabolic flexibility. Conversely, elevated ketone concentrations may result from fasting, prolonged exercise, exogenous ketone supplementation, or sodium-glucose cotransporter-2 (SGLT2) inhibitor therapy, each reflecting different physiological contexts (Anton et al., 2018;Brown et al., 2021). By integrating both measures, the GKI reflects the physiological response to nutritional and metabolic interventions rather than dietary adherence alone (Lee et al., 2026) The two variables comprising the GKI are not merely markers of substrate availability; they exert opposing effects on the mitochondrion, the organelle at the center of the metabolic dysfunction described above. Sustained hyperinsulinemia promotes ceramide accrual and impairs mitochondrial respiration in insulin-sensitive tissues, and in brown adipose tissue it reduces mitochondrial uncoupling in a manner that lowers energy expenditure (Dallon et al., 2018). BHB exerts the opposite effect, increasing mitochondrial respiration in adipose tissue while reducing reactive oxygen species emission and mitochondrial fission (Walton et al., 2020). Viewed this way, the GKI reflects not only which fuel predominates but the bioenergetic consequence of that predominance, offering a mechanistic rationale for the link between the index and mitochondrial function proposed by Lee et al.A related consideration is that both terms of the ratio are governed by a common upstream regulator. Insulin restrains lipolysis and hepatic ketogenesis at concentrations well below those required to lower circulating glucose (Petersen and Shulman, 2018), so ketone production is suppressed long before glycemia rises. The GKI therefore functions in part as an accessible surrogate for the ambient insulin state, which is rarely measured in routine practice despite hyperinsulinemia preceding hyperglycemia by years in the natural history of insulin resistance. This interpretation clarifies why glycemic improvement achieved pharmacologically may leave the GKI largely unchanged, and why interventions that lower insulin-whether nutritional, behavioral, or pharmacologic-move both terms of the ratio in the same favorable direction. This distinction becomes increasingly important as precision nutrition moves beyond dietary prescriptions toward individualized metabolic responses (Zeevi et al., 2015