Abstract
The chronic disease burden is rapidly becoming the most significant health challenge of the 21st century. Chronic noncommunicable diseases (NCDs) are replacing infectious diseases as the most significant factor in poor global health outcomes. NCDs account for 75% of disability adjusted life years. Cancer is one of the deadliest chronic diseases and is now on the verge of overtaking heart disease as the leading cause of death in the United States. Mitochondrial dysfunction linked to nutritional imbalance, lack of physical activity, and exposure to a broad range of environmental toxins is implicated in cancer and many chronic diseases. Although nutrition and exercise recommendations have been emphasized for primary prevention, overall health remains poor due to conflicting information and the inability to easily assess adherence. The glucose ketone index (GKI) was originally developed as a quantitative point-of-care blood biomarker for assessing diet adherence in cancer therapy. However, the ratio of glucose to ketones (specifically β-hydroxybutyrate) can also be linked to the risk of chronic diseases and may help predict risk more accurately than the glucose reading alone. Low GKI ratios are hypothesized to decrease risk, while high GKI are hypothesized to increase risk. Non-insulin-compensated euglycemia may help reduce chronic inflammation, insulin resistance, and pro-tumorigenic pathways. Endogenous ketone production reduces glucose requirements while simultaneously enhancing the bioenergetic efficiency of mitochondrial energy metabolism, thus supporting metabolic homeostasis. Hence, we assert that the GKI could represent a parsimonious, individualized, and impartial biomarker for use, together with exercise and nutrition, to support therapeutic strategies to prevent and manage mitochondrial dysfunction, which contributes to cancer and many chronic diseases.
Key points
Mitochondrial dysfunction is defined as insufficient adenosine triphosphate (ATP) production through oxidative phosphorylation (OxPhos) in response to energy demand. OxPhos insufficiency, linked to excess production of reactive oxygen species (ROS), is implicated in many chronic diseases, including cancer, cardiovascular diseases, type 2 diabetes, obesity, and neurodegeneration.
The ketone body β-hydroxybutyrate (βHB) has been designated a “super fuel” because it is more effective than either pyruvate or fatty acids in enhancing the bioenergetic efficiency of mitochondrial ATP production.
The glucose ketone index (GKI), which measures the ratio of blood glucose levels to βHB levels, may be a useful biomarker for assessing nutritional ketosis over time in the outpatient setting.
A shift in mitochondrial metabolism from glucose to βHB may reduce systemic inflammation, hyperglycemia, hyperinsulinemia, and ROS production.
The GKI, used together with science-based nutrition and exercise, could provide a monitoring tool for improving mitochondrial health and restoring metabolic homeostasis, thereby supporting the prevention and management of cancer and chronic diseases.
Introduction
The global disease burden is projected to shift from infectious diseases to chronic noncommunicable diseases (NCDs) over the next several decades, cementing NCDs as the next major global public health challenge (, ). NCDs may account for upward of 75% of all disability-adjusted life years and lead to decreases in life expectancy (). Cancer, hypertensive heart disease, and Alzheimer's disease (AD) are the most common NCDs whose burden is forecast to rise worldwide by 2050 (, ). The rise of NCDs can be significantly blunted by reducing metabolic risk factors, including high body mass index, elevated triglycerides, high blood pressure, hyperinsulinemia, and elevated fasting plasma glucose (, ).
The United States is projected to fall behind other comparable countries in health outcomes due to NCDs (). Chronic NCDs account for 8 out of 10 leading causes of death in the United States despite improvements in public health (). Cancer is now on the verge of overtaking heart disease as the leading cause of death (). Projections indicate that cancer will claim over 626,000 lives in the United States in 2026, equivalent to over 1,700 deaths per day or 70 deaths per hour (). The anti-smoking campaign of the 1990s was largely responsible for preventing even steeper increases in cancer mortality (). New global public health initiatives for primary and secondary prevention may be the next major frontier for blunting the annual increase in chronic disease-related deaths.
Life expectancy in the United States remains lower than that in other developed nations (). The increased prevalence of chronic diseases among Americans is hypothesized as a major reason for this disparity (). The increasingly aging population may partially account for the chronic disease epidemic (). Indeed, approximately 20% of Americans will be aged 65 years or older by 2030, compared with just 13% in 2012 and 4.1% before 2000 (). However, the incidence of chronic disease has increased across nearly all age groups, including children (, ). For example, the incidence of childhood cancer has increased by 33% since 1975 (). The growing burden of chronic diseases must be rapidly addressed in order to improve both healthspan and lifespan across global demographics (, ).
Non-modifiable risk factors of chronic disease include sex, age, and genetic predisposition (–). Modifiable risk factors include smoking, poor nutrition, poor sleep, psychological stress, and low physical activity (, ). Although smoking and alcohol consumption have declined in younger demographics, poor nutrition and reduced physical activity remain the most consequential preventable risk factors (, ).
Abundant evidence illustrates that a lack of physical activity and poor nutrition are major drivers of the chronic disease epidemic in the United States and other developed nations (, –). For example, over half of Americans are overweight or obese, with projections showing this will exceed two-thirds of adults by 2050 (, ). Mortality related to excess adiposity is associated with nearly 500,000 deaths per year in the United States (). Hence, accurate nutritional information together with increased physical activity becomes a logical path for improving health (, ).
Emerging evidence suggests that many chronic diseases, including cancer, type 2 diabetes (T2D), obesity, psychiatric disorders, and hypertensive heart disease, are attributable to or are significantly influenced by mitochondrial dysfunction, i.e., the inability to regulate efficient adenosine triphosphate (ATP) production through oxidative phosphorylation (Oxphos) in response to energy demand (–). Indeed, mitochondrial dysfunction plays a critical role as both a cause and effect of disease, emphasizing the non-linear progression of chronic disease over time (). This article introduces the glucose ketone index (GKI) as a biomarker that may enable clinicians, researchers, and patients to assess long-term nutritional adherence and thereby support metabolic approaches for the prevention and management of chronic diseases and cancer. We review the detrimental links between chronic hyperglycemia, pro-inflammatory cascades, and hyperinsulinemia. Additionally, we describe the mechanistic basis by which β-hydroxybutyrate (βHB) reduces oxidative stress while enhancing the efficiency of mitochondrial ATP production compared with either pyruvate or fatty acids. Furthermore, we discuss the non-metabolic roles of βHB, including mitochondrial network morphology maintenance and anti-inflammatory signaling. We propose that the GKI, derived from measuring the ratio of glucose to βHB in plasma, may provide additional insight into systemic metabolism compared with conventional markers such as body weight or more subjective blood biomarkers. We suggest that nutritional ketosis, as assessed by the GKI, may be a broadly applicable strategy for decreasing both chronic hyperglycemia and hyperinsulinemia while simultaneously increasing endogenous βHB production, enhancing the general efficiency of mitochondrial energy production and overall health.
Ketogenic metabolic therapy for managing cancer and chronic disease
Ketogenic metabolic therapy (KMT), involving ketogenic diets (KDs), time-restricted feeding, and water-only fasting, has been proposed for the management of cancer and many chronic diseases (–). High-fat, low-carbohydrate KDs were first established as the preferred treatment for drug-resistant epilepsy in the early 20th century (). Since then, KDs have been explored as an intervention for numerous conditions, including type 1 and type 2 diabetes (46), neurodegeneration (, ), Parkinson’s disease (, 50), obesity (51), cardiovascular disease (52), psychiatric disorders (including autism spectrum disorder), (53–57), and cancer (, 58–60). Proposed mechanisms vary between diseases but coincide in weight loss or stabilization, hormonal regulation, reduced inflammation, oxidative stress control, and euglycemia (, 61–65). Despite preliminary evidence from preclinical and early clinical reports, KMT is not currently used for chronic disease management at scale.
The GKI was initially developed as a simple tool for the metabolic management of brain cancer, where it has received the most use (, 58–60, 66–69). As mitochondrial dysfunction is a common pathophysiological characteristic of most major cancers, the GKI may be useful as a tool for the metabolic management of most cancers (, , 58). βHB and glucose can both be measured by finger-prick or continuous monitoring devices (, 58, 70). Our aim is to describe the rationale for using the GKI as a self-directed tool to help standardize and improve adherence to nutritional ketosis in order to maintain stable low euglycemia (, ). Chronic hyperglycemia has deleterious metabolic consequences, including hyperinsulinemia leading to insulin resistance (71, 72), systemic inflammation (73, 74), and increased risk of cardiovascular disease (75). Conversely, βHB provides a bioenergetically superior fuel to glucose and fatty acids, with additional anti-inflammatory benefits (, 50, 76–79). We assert that the GKI could emerge as a biomarker to support the management of some types of mitochondrial dysfunction, which may contribute to cancer and many other chronic diseases.
Mitochondrial dysfunction: the origin of cancer and chronic diseases
Mitochondria are essential for metabolic homeostasis, i.e., the ability to maintain a stable internal cellular environment (80–82). Mitochondrial structure and function are closely linked (83, 84). Abnormalities in mitochondrial number, structure, and function can disrupt metabolic homeostasis and are implicated in some chronic diseases ranging from obesity and diabetes to cardiovascular disease and cancer (, , 81, 85–87) (Figure 1). Mitochondrial dysfunction involves the inability to regulate efficient ATP production through Oxphos in response to energy demand (88–91). OxPhos produces the majority of ATP within the mitochondria of growth-regulated normal cells (92, 93). Briefly, acetyl coenzyme A (acetyl-CoA) enters the tricarboxylic acid (TCA) cycle, producing the reducing equivalents nicotinamide adenine dinucleotide (NADH) and succinate (via flavin adenine dinucleotide; FAD) with carbon dioxide as a byproduct. NADH and succinate donate electrons to coenzyme Q (CoQ) through complex I and II, respectively (Figure 2A). CoQ transports electrons to complex III. Cytochrome c accepts electrons from complex III and transfers them to complex IV. Complex IV utilizes oxygen as the terminal electron acceptor, producing water as a byproduct. The transfer of electrons through complexes I, III, and IV drives the pumping of protons from the matrix into the inner mitochondrial space, thus creating the electrochemical gradient needed for ATP synthesis (92, 94, 95). Complex V (the F1F0 ATPase) couples the translocation of protons back into the mitochondrial matrix with the phosphorylation of adenosine diphosphate (ADP) to ATP (96). Efficient ATP production through OxPhos is essential for maintaining adequate energy for enzymatic processes and metabolic homeostasis.
Figure 1
Figure 2
Several factors can cause inefficient OxPhos, including proton leak, uncoupling, substrate shortage or overabundance, mutations in the electron transport chain (ETC), and intermittent oxygen deficiency (92, 95, 97–101). Inefficient energy production through OxPhos produces relatively high concentrations of reactive oxygen species (ROS) (102, 103). ROS travel to the nucleus and facilitate transcriptional adaptations to stimuli such as transient oxygen deprivation or nutrient imbalance (104, 105). Most importantly, excess ROS are carcinogenic and mutagenic, contributing to the somatic mutations and genomic instability observed in most cancers (, 106–109). Hence, prolonged ROS formation that exceeds intracellular antioxidant systems can have a negative impact on mitochondrial function, heightening the risk of chronic diseases and cancer (109–111).
Abnormalities in mitochondrial structure and function are observed in most major cancers and in many chronic diseases, including diabetes, cardiovascular disease, obesity, and psychiatric disorders (, 112–118) (Figure 1). ETC complexes are transmembrane proteins that are embedded within the cristae, invaginations of the inner mitochondrial membrane that increase the surface area for ATP production (119–121). The maintenance of mitochondrial structure is a continual, dynamic process that undergoes cycles of fusion, fission, and mitophagy (122, 123). Mitochondrial fusion induces mitochondrial elongation and pro-oxidation metabolism, while fission results in mitochondrial fragmentation and loss of cristae (120, 124) (Figure 1). Mitophagy is a form of autophagy that degrades damaged or dysfunctional mitochondria (123). Defective mitophagy signaling disrupts mitochondrial homeostasis, leading to pathology (125). While less severe diseases, e.g., obesity, insulin resistance, and T2D, may allow for natural repair of mitochondrial function over time by removing or mitigating the chronic mitochondrial injury, other diseases, e.g., advanced neurodegenerative diseases, may be beyond an arbitrary irreversible threshold of mitochondrial damage and cell death (126). Mitochondrial transplantation is a nascent yet promising alternative strategy for either severe or irreversible chronic diseases (127). Consequently, the integrity of mitochondrial structure is essential for the efficiency of mitochondrial function. The following sections outline the evidence for the pathophysiological role of mitochondrial dysfunction in cancer and various chronic diseases.
Cancer
New information, building on Warburg’s original hypothesis, supports a model in which cancer can arise from mitochondrial dysfunction in a two-step process (, 97). The first step involves a chronic insufficiency of OxPhos, while the second step involves a protracted compensatory energy synthesis through oxygen-independent substrate-level phosphorylation (SLP) in the cytosol and in the mitochondria (). The sugar glucose and the amino acid glutamine are fermented for energy through upregulation of the glycolysis and the glutaminolysis pathways, respectively (128–131). In contrast to the transient extracellular accumulation of fermentation end products seen in oxygen-deprived normal cells, most tumor cells chronically produce lactate and succinate as metabolic end-products of glucose and glutamine fermentation, respectively, even in the presence of oxygen (, 130, 132–134). The extracellular accumulation of these metabolic end-products contributes to the acidification of the tumor microenvironment, therapy resistance, and tumor progression (134–136). In other words, the continuous elevation of cytosolic SLP with lactate production and mitochondrial SLP with succinate production are both effects of chronic OxPhos insufficiency, i.e., the bioenergetic signature of most major cancers (). As OxPhos sufficiency controls the differentiated state and the cell cycle, chronic OxPhos insufficiency is often linked to dedifferentiation and dysregulated cell proliferation, i.e., cancer (, 137).
All major cancers have documented metabolic abnormalities in the number, structure, or function of mitochondria that compromise the efficiency of OxPhos, contributing to a common metabolic phenotype (138). Consistent with these abnormalities, ETC complexes are downregulated in many cancers (139, 140). In gastric cancer and glioblastoma, for example, complex I or III downregulation increases ROS and pro-glycolytic signaling (141, 142). Complex V subunits were downregulated in 23 out of 29 clear cell renal cell carcinomas, when compared with normal renal tissue (143). Moreover, no tumor has yet been found with a normal content or composition of cardiolipin, the inner mitochondrial membrane-enriched phospholipid that is essential for efficient OxPhos function (, 144–146). Abnormalities have also been reported in neoplasms for mitochondrial coenzyme Q, which, like cardiolipin, is also essential for OxPhos efficiency (, 147–150). Consequently, compromised mitochondrial membrane structure, lipid composition, and ETC expression result in a bioenergetic deficit, leading to insufficient OxPhos.
As energy is a central issue in cancer, chronic OxPhos insufficiency necessitates compensatory cytosolic and mitochondrial SLP to maintain sufficient ATP content for viability and growth (97, 130, 138). Tumors ferment most glucose-derived pyruvate to lactate and much of the glutamine to succinate regardless of oxygen availability, rather than fully oxidizing pyruvate and succinate through the TCA cycle. Cancer cells consume more glucose and glutamine than do healthy quiescent cells to support their fermentation metabolism and synthesis of growth metabolites (130, 151, 152). Indeed, [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) is used as a diagnostic tool for measuring excessive glucose uptake into cancer cells (153, 154). Finally, triglyceride lipid droplets are stored in the cytoplasm of all major cancers as a consequence of insufficient OxPhos, making lipid droplets a biomarker for dysfunctional mitochondria (, 155). The distinct metabolic differences between cancer cells and healthy cells may be useful for diagnosis, monitoring, and treatment (, 58).
Type 2 diabetes and obesity
Dysregulated mitochondrial dynamics and metabolism are also found in people living with T2D, metabolic syndrome, and obesity (156, 157). The link between insulin resistance, T2D, and obesity is well-established (158). An overabundance of intracellular nutrients can overwhelm metabolic pathways, thus reducing the efficiency of mitochondrial ATP production while increasing ROS production (). Maximal mitochondrial respiration is lower in people living with obesity and fatty liver disease than in lean patients (159). Furthermore, mitochondrial biogenesis and OxPhos proteins are downregulated in the adipose tissues of people living with obesity (160, 161). Mitochondrial dysfunction may be the underlying cause of the deleterious effect of excess adipose tissue (117, 162, 163). Although fat storage in adipose tissue is an evolutionary adaptation to food scarcity and is responsible in part for human survival during the Paleolithic period, minimal physical exercise and modern accessibility to processed high-glycemic carbohydrates have created a biological mismatch often leading to insulin insensitivity, T2D, metabolic syndrome, chronic disease, cancer, and ultimately reduced lifespan (164–166).
Impaired insulin sensitivity in people with T2D is linked to lower ATP levels and higher uncoupling protein expression in pancreatic islet cells, which regulate insulin release (163, 167, 168). Increased mitochondrial fission elevates ROS and inflammatory markers in patients with T2D (169, 170). Accordingly, complex I activity is lower in the skeletal muscle of patients with T2D than in that of healthy controls (171, 172). Proteomic-wide analysis found that complexes I, III, IV, and V were significantly lower in both pre-diabetic and diabetic men than in men with normal glucose tolerance (173). The catalytic β-subunit of complex V was downregulated in skeletal muscle biopsies of T2D cohorts (174, 175). Together, this evidence suggests that metabolic defects in mitochondria can drive the pathophysiology observed in both obesity and T2D.
Hypertension-linked cardiovascular disease
Overactivation of the renin–angiotensin system (RAS) has been linked to hypertension, cardiovascular disease, and mitochondrial dysfunction (176). Obesity, physical inactivity, and sodium-rich, high-glycemic carbohydrate foods activate the RAS (176–178). Chronic RAS activation stimulates the sympathetic nervous system, cortisol and aldosterone release, vasoconstriction, and excess secretion of anti-diuretic hormone, all of which lead to hypertension (179, 180). Hypertension-induced cardiomyocyte hypertrophy is closely linked to adverse cardiac events (181, 182). Hence, RAS-induced hypertension exacerbates cardiovascular disease.
Hypertension-induced cardiomyocyte hypertrophy results in mitochondrial cristolysis, leading to ETC dysfunction and excess ROS production (183–186). Hypertrophy alters substrate utilization in cardiomyocytes, decreasing glucose and fatty acid oxidation (187–189). Instead, glucose utilization is partially shunted toward lactate production, lowering the efficiency of mitochondrial OxPhos (190, 191). Hypertrophy also induces ETC uncoupling, further reducing the efficiency of ATP production through OxPhos (192). Complex V downregulation depletes ATP content, contributing to heart failure (193, 194). Whereas cancer cells gradually upregulate glucose and glutamine fermentation to compensate for OxPhos insufficiency, OxPhos insufficiency can lead to energy crisis and cell death in hypertrophic cardiomyocytes (, 195, 196). Thus, mitochondrial dysfunction is an important contributor to hypertension-linked cardiovascular disease (197).
Alzheimer’s disease
AD is classified as a neurodegenerative disease associated with memory loss, behavioral impairment, and cognitive challenges (198–200). AD is also considered “type 3 diabetes” owing to the role of hyperinsulinemia, glucose hypometabolism, and mitochondrial dysfunction in its pathophysiology (126, 201). Evidence suggests that AD arises from long-term disruption of mitochondrial function in neurons (126, 202, 203). Neurons are a major consumer of ATP in vivo due to synaptic vesicle loading, action potential firing, and ionic gradient balance (204, 205). Neurons exhibit short-term flexibility between glycolytic and oxidative metabolism to compensate for increased ATP demand (206). However, high long-term ATP demand disrupts sodium/potassium (Na+/K+)-ATPase activity, causing excitotoxicity, suggesting a bioenergetic vulnerability that leads to neurodegeneration and cell death (207, 208). Interestingly, glycolytic hypometabolism presents alongside or prior to classical AD symptoms (209–211). Region-specific cerebral hypometabolism is a reliable test of synaptic dysfunction in AD progression (212–214). Dysfunctional energy metabolism is therefore a central driver of AD-associated neurodegeneration.
ETC complexes are compromised in both pre-clinical models and clinical AD (, 215, 216). Complex V activity is lower in patients with early-stage AD (217, 218). Furthermore, amyloid plaques directly inhibit the complex V α-subunit, further reducing ATP production (219, 220). Neurofibrillary tau tangles, a diagnostic hallmark of AD, are associated with decreased complex I activity (221). Apolipoprotein E4, a genetic risk factor for AD, reduces complex IV expression and lowers mitochondrial respiratory capacity (222, 223). Collectively, these data indicate that mitochondrial dysfunction is compromised in both early- and late-stage AD.
Psychiatric disorders
Mitochondrial dysfunction is also connected to several psychiatric conditions, including bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD) (224–226). The brain comprises 2–3% of body mass, yet consumes 20–25% of circulating glucose in non-ketotic states, underscoring its vulnerability to metabolic perturbations (76, 227, 228). Psychiatric symptoms can first manifest in otherwise undiagnosed patients due to early mitochondrial dysfunction (229, 230). Indeed, the incidence of clinical depression is increased in adolescents with mutations in proteins that govern mitochondrial metabolism (231, 232). Current research suggests that mitochondrial dysfunction is a critical factor underlying the increasing incidence of psychiatric disorders.
Both environmental and genetic disruptions of OxPhos may contribute to the increase in neuropsychiatric disorders (233). In pediatric ASD, OxPhos deficiency is associated with decreased cardiolipin, ganglioside content, coenzyme Q, and antioxidants (234). Additionally, ETC complexes I and V are downregulated in both adults and children with ASD (235). Likewise, reduced TCA cycle and ETC complex activity are observed in cohorts with SCZ and BD (236–239). Lactate accumulation, a metabolic signal of OxPhos insufficiency, is elevated in the brains of patients with SCZ, BD, and ASD (240–242). Increased oxidative stress, linked to impaired OxPhos metabolism, exceeds antioxidant capacity, and causes bioenergetic stress that manifests as behavioral abnormalities, inflammation, and neuronal instability (243–245). Hence, mitochondrial dysfunction is linked to several psychiatric disorders, including BD, SCZ, and ASD (228).
Hyperglycemia drives chronic diseases
Hyperglycemia is clinically defined as fasting blood glucose levels above 125 mg/dL and postprandial blood glucose levels above 180 mg/dL for 2 h or more (246). The detrimental link between chronic hyperglycemia, hyperinsulinemia, and T2D is well-recognized and poses significant challenges for clinicians (75, 168, 247–249). Moreover, systemic inflammation is another consequence of chronic hyperglycemia (73, 250, 251). Chronic hyperglycemia causes persistent upregulation of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukins (IL), including IL-1β and IL-6 (252, 253). Although acute IL-6 elevation supports normal glucose metabolism, chronic IL-6 elevation is linked to systemic inflammation (252). Sustained IL-6 and TNF-α signaling stimulates the release of liver-derived C-reactive protein (254, 255). C-reactive protein further elicits inflammatory responses observed in T2D and cancer (256, 257). Systemic inflammation is therefore another consequence of chronic hyperglycemia contributing to chronic disease (258).
Insulin resistance, linked to hyperglycemia, is also a major risk factor for T2D, obesity, atherosclerosis, liver disease, cancer, and other metabolic diseases (72, 259–262). Chronic overconsumption of highly palatable carbohydrates can contribute to excessive insulin secretion and eventual insulin resistance (, 263, 264). Both impaired glucose uptake and altered phosphatidylinositol 3-kinase–AKT–mammalian target of rapamycin (PI3K–AKT–mTOR) signaling contribute to insulin resistance pathophysiology (265–267). Hyperinsulinemia and obesity are closely associated with increased incidence and mortality across many cancers (268, 269). Insulin insensitivity results in increased basal insulin levels and prolonged oxidative stress, impairing both glucose and lipid metabolism (270–272). Oxidative stress, as a marker of dysfunctional mitochondrial metabolism, is linked to cardiac disease, cancer, neurodegeneration, and other chronic diseases (, 110, 250, 273, 274). Therapeutic strategies that can reduce chronic hyperglycemia without endogenous or exogenous insulin can improve insulin sensitivity and can benefit people living with chronic diseases and cancer.
Synthesis and metabolism of ketone bodies
Although glucose is the primary energy substrate for most cells when available, ketone bodies can replace glucose during periods of prolonged exogenous glucose restriction (275–277). Liver hepatocytes metabolize fatty acids to produce the ketone bodies βHB and acetoacetate (AcAc) together with acetone as a non-enzymatic byproduct (278, 279). Circulating βHB concentrations range from <0.1 mM under normal fed conditions and increase to over 6 mM in physiological ketosis (64, 79, 280). Notably, physiological or nutritional ketosis differs from diabetic ketoacidosis, a rare pathological condition in which high circulating levels of glucose (>13.9 mM) and ketone bodies (>15 mM) coexist in the presence of decreasing bicarbonate levels (indicating insulin insufficiency) and which is more commonly seen in type 1 diabetes than in T2D (281, 282). Most cells can utilize βHB for ATP synthesis, except for mature erythrocytes and hepatocytes (283). Erythrocytes lack mitochondria, which are required for ketone body utilization (284). Conversely, hepatocytes contain mitochondria but lack the succinyl-CoA:3-oxoacid-CoA transferase (SCOT) enzyme needed for ketone body metabolism (283). βHB and to a lesser extent AcAc, are transported to extrahepatic tissues and enter cells via monocarboxylate transporter 1 (79, 285). β-hydroxybutyrate dehydrogenase (BDH1) converts βHB to AcAc to produce NADH as the first step of ketolysis (Figure 3). BDH1 is localized to the mitochondrial membrane (279). Next, AcAc is converted to acetoacetyl-CoA (AcAc-CoA) via SCOT. As the name implies, a CoA group is donated using succinyl-CoA as a substrate, producing succinate as a byproduct. Finally, AcAc-CoA is split into two acetyl-CoAs by mitochondrial acetyl-CoA transferase (ACAT). Acetyl-CoA serves as an anaplerotic substrate for the TCA cycle, producing NADH and succinate. Pyruvate-derived acetyl-CoA produces an estimated 10 ATP/mol, whereas βHB-derived acetyl-CoA produces an estimated 13 ATP/mol, making βHB a more energy-rich fuel than pyruvate (77, 286). Importantly, glucose-derived TCA cycle intermediates facilitate ketone body utilization despite the inhibitory effect of βHB on pyruvate dehydrogenase, illustrating the metabolic interplay between both pathways (286, 287).
Figure 3
βHB as a bioenergetic “super fuel”
Veech and colleagues first described βHB as a “super fuel”, as the heat of combustion derived from it exceeds that from pyruvate (−487.2 ΔH°kcal and −278.5 ΔH°kcal, respectively) (76, 77). The greater combustion of βHB results from its greater hydrogen:carbon ratio, i.e., there are two hydrogen atoms per carbon atom in βHB versus 1.3 in pyruvate. Accordingly, βHB yields more energy per C2 unit (−243.6 ΔH°kcal) than either pyruvate (−185.7 ΔH°kcal) or glucose (−223.6 ΔH°kcal) (77). Thermodynamic comparisons between metabolic substrates, however, are important only when evaluated within the context of OxPhos (Figure 2A).
Ketone bodies are increasingly recognized as a premier substrate for ATP synthesis (50, 76, 287). βHB reduces the Gibbs free energy change (ΔG’) of the CoQ couple by reducing the mitochondrial NAD+/NADH ratio while oxidizing the CoQ/CoQH2 (the reduced form of CoQ) ratio (288, 289) (Figure 2B). CoQ/CoQH2 is approximated by the succinate/fumarate ratio (288). Accordingly, βHB utilization increases the concentration of succinate in isolated mitochondria. Increased succinate boosts ATP content via complex II while under complex I inhibition (290). Furthermore, βHB and nutritional ketosis elevate succinate concentration and complex I and II activity, which protects the brain from cerebral ischemia (291, 292). In the heart, glycogen-derived glycolytic flux increases βHB oxidation, thus increasing the mitochondrial redox potential, ultimately increasing the free energy of ATP hydrolysis (287). These findings warrant the view that βHB is a metabolic “super fuel”.
ΔG’ of ATP hydrolysis: the “still point in the turning world”
Export of mitochondrial ATP to the cytoplasm raises the ΔG’ of ATP hydrolysis (77, 288). A more negative ΔG’ reflects a larger redox span, making reactions more thermodynamically favorable. Increased redox span enhances the driving force for mitochondrial electron transport, yielding more ATP per mol of substrate (50). The cytoplasmic ΔG’ of ATP hydrolysis is tightly regulated between −56 kJ/mol and −59 kJ/mol, and it is not dependent on whether ATP is synthesized in the mitochondria or in the cytoplasm (50). This range is constant, whether the cell is a mitochondria-free erythrocyte or a mitochondria-laden cardiomyocyte (293). ATP consumption is regulated by energy-demanding processes, such as the maintenance of inorganic ion gradients across the plasma membrane (294). Veech described the cytoplasmic ΔG’ of ATP hydrolysis as the “still point in the turning world” (50). Although redox states for NAD(P) vary appreciably, the ΔG’ of ATP remains within narrow limits and underlies both genetic and metabolic processes, all of which are embodied in the second law of thermodynamics (). Hence, an increased supply of reactants for individual reactions, such as ATP synthesis or hydrolysis, results in higher metabolic efficiency.
Fatty acids are less efficient than ketone bodies for energy production
In contrast to ketone bodies, which enhance coupling of OxPhos to ATP production, excess fatty acids may uncouple OxPhos through proton leak via adenine nucleotide translocase and the family of uncoupling proteins (295–301). On the other hand, ketone body metabolism produces a slightly steeper electrochemical gradient without activation of uncoupling proteins (77). Nevertheless, fatty acids produce n/2 acetyl-CoAs, where n is equal to the number of carbon atoms. Palmitic acid, for example, contains 16 carbons, which break down through iterative cycles of β-oxidation, donating high amounts of electrons via NADH. β-oxidation also donates electrons to CoQ via electron transfer flavoprotein dehydrogenase (ETF-Qo), bypassing complex II (302). A high electrochemical gradient suppresses the CoQH2 oxidation at the Qo site of complex III, hindering forward electron transport (103). Thus, fatty acids decrease the ΔG’ of ATP by reducing both the NAD+/NADH and the CoQ/CoQH2 ratios (303) (Figure 2C).
Ketone body metabolism reduces ROS production
ROS arise primarily when the unpaired electron of semiquinone (CoQH) reacts with molecular oxygen to generate superoxide anions (O2−) (304, 305). Superoxide anions are produced within the ETC during CoQ- or bound flavin-mediated [i.e., FAD and flavin mononucleotide (FMN)] electron transfer; these sites include IF and IQ in complex I, IIF and IIQ in complex II, and Qo and Qi in complex III (95, 306–308). While CoQH is normally a short-lived intermediate under basal conditions, its half-life increases during ETC inhibition or reverse electron transfer (RET) (309, 310). Other primary ROS include hydrogen peroxide (H2O2) and the hydroxyl radical (OH−), with the hydroxyl radical being the most reactive and damaging (305, 311).
Although complexes I–V generally operate in the forward direction, they can on occasion operate in the reverse direction. RET is a significant source of ROS production in pathological disease states (310, 312). Complex V reversal hydrolyzes, rather than synthesizes, ATP during RET to maintain mitochondrial membrane potential (313, 314). A primary cause of RET is when the CoQ/CoQH2 ratio becomes too reduced, decreasing the efficiency of the CoQ cycle (315). βHB-mediated ROS mitigation is due in part to the elevated ΔG’ of ATP without significant reduction of the CoQ/CoQH2 ratio (289). Moreover, βHB reduces the cytosolic NADP+/NADPH couple, which is in near equilibrium with the reduced and oxidized glutathione couple. The reduced form of glutathione is a master regulator of intracellular oxidative stress (77, 316). Therefore, βHB reduces intracellular ROS by promoting forward electron transport and increasing reducing equivalents for superoxide scavenging.
βHB reduces inflammation while increasing mitochondrial function
βHB serves several signaling functions in addition to its role as an ATP-generating metabolite (79). βHB inhibits several classes of histone deacetylases (317, 318). Histone acetylation induces expression of the forkhead box protein O3 (Foxo3a) and metallothionein-2 (Mt2) genes, which regulate inflammation and attenuate oxidative stress (317). Foxo3a and Mt2 downregulation is observed in carcinogenesis and inflammatory cascades (319, 320). Furthermore, βHB inhibits the nucleotide-binding oligomerization domain (NOD)-like protein 3 (NLRP3) inflammasome, a potent activator of pro-inflammatory cytokines in T2D and obesity (321, 322). Finally, βHB suppresses stress-induced NLRP3-mediated production of the pro-inflammatory cytokines IL-1β and TNF-α (323). Hence, βHB exerts direct effects on the expression of genes influencing inflammatory pathways, including Foxo3a, Mt2, and the NLRP3 inflammasome.
Emerging preclinical evidence suggests βHB stimulates fusion of the mitochondrial network in skeletal muscle, thus improving function (324, 325). Long-term βHB supplementation increases exercise capacity by elevated expression of optic atrophy 1 (OPA1), a regulator of mitochondrial cristae structure and energy production (326). Ketone ester supplementation rescues mitochondrial biogenesis and mitophagy deficits in diabetic mice (327). βHB increases expression of Parkin and other mitophagy markers to limit mitochondrial fragmentation in a model of cardiovascular disease (328). Ultimately, mitochondrial morphology maintenance is essential for healthy mitochondrial function (84). The multimodal benefits of endogenous nutritional ketosis are summarized in Figure 4.
Figure 4
The glucose ketone index: a quantitative metabolic measure for monitoring nutritional ketosis in cancer and chronic disease management
The GKI measures the millimolar ratio of circulating glucose to ketone bodies (βHB) and is used to quantify the degree of nutritional ketosis (, , 60, 68, 329). We originally hypothesized that maintaining GKI values of 1.0–2.0 or below would be favorable for managing cancer, translating to numerous clinical reports of improved overall survival (, 58, 60, 66, 329). However, we predict that higher GKI values may be effective for the prevention or management of other chronic diseases. Consequently, we have developed a color-coded GKI chart that proposes zones for studying and monitoring nutritional ketosis in chronic disease and cancer (Figure 5). We hypothesized the range of each zone based on where an individual would fall with respect to their relative adherence to nutritional ketosis (endogenous ketogenesis). For example, an individual who does not restrict carbohydrate intake may have a GKI of 50 (red zone), derived from 5.0-mM glucose and 0.1-mM ketones readings. An individual in moderate ketosis may have a GKI of 10, derived from 5.0-mM glucose and 0.5-mM ketones (yellow zone) readings. Finally, an individual who is in deep ketosis may have a GKI of 2, derived from 4.0-mM glucose and 2.0-mM ketones (green zone) readings. Given that elevated endogenous ketogenesis during nutritional ketosis is a binary physiological state induced by sufficient carbohydrate restriction and low insulin, these ranges were constructed based on the observable and evolutionarily conserved physiological effects of sustained carbohydrate restriction (330). The proposed zones are subject to change as future clinical data are collected, e.g., a GKI of 10 may be suitable to improve insulin sensitivity and manage systemic inflammation but may not be low enough to arrest the growth of most tumor cells. Moreover, disease-specific benefits are likely to arise if a longer time is spent in a given zone, rather than through strict adherence to a specific value. Periods of a low GKI (simulating carbohydrate “famine”) interspersed with transient elevations in GKI (reflecting carbohydrate “feast”) may better represent the ancestral feast and famine cycles in accordance with evolutionary biology (331–335). As mitochondrial dysfunction is frequently observed in cancer and many chronic diseases, the GKI chart may serve as a self-managed guide for monitoring nutritional ketosis, supporting strategies aimed at improving mitochondrial function for the management of cancer and chronic diseases.
Figure 5
In the following sections, we highlight the practical importance of macronutrients, micronutrients, physical activity, and managing psychological stress in modulating the GKI.
Macronutrients
Macronutrient optimization is the first, and most critical, step toward achieving sustainable metabolic health (Figure 6). A very-low-carbohydrate (<20 g/day), high-fat (to satiety), and adequate high-quality protein (0.8–2.0 g/kg/day) diet is considered important for sustaining low GKI values (336). Alternative dietary strategies, such as Mediterranean or plant-based diets, may share some effects on mitochondrial function through calorie restriction and sporadic low GKI due to fasting schedules, but these may lack a real-time biological readout of adherence. The GKI was constructed to be food composition agnostic, i.e., any nutritionally balanced diet could lead to improved GKI ranges compared to highly insulinogenic, ultra-processed Western diets. In other words, the GKI removes the guesswork as to whether consumption of a particular food item can produce a state of nutritional ketosis.
Figure 6
Muscle mass maintenance is critical for patients with many chronic diseases, such as age-related sarcopenia and cancer-associated cachexia (337, 338). Adults typically consume less than the recommended daily allowance of high-quality protein necessary for muscle mass maintenance and synthesis (339–342). Protein-rich meals produce only modest gluconeogenic responses in healthy cohorts (343). In contrast to carbohydrate-rich foods, protein-rich foods stimulate anti-hunger hormones, including glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK), thereby promoting satiety (65, 344–346). The optimal ratio of dietary fat to protein will vary depending on metabolic condition, individual experience, and degree of ketogenic adaptation (347).
Several limitations exist for more ubiquitous use of ketogenic approaches. Critically, low adherence to strict ketogenic diets could be partially attributable to temporary unpleasant side effects, including electrolyte imbalance, dehydration, rare instances of hypersensitivity (e.g., prurigo pigmentosa), or gastrointestinal distress during ketogenic adaptation. Gradual reduction in total carbohydrate as well as proactive adjustments in fluid intake, electrolyte supplementation (sodium, chloride, potassium, calcium, and magnesium), or fat-to-protein ratios may mitigate some temporary adverse effects (348–350). It is also important to contrapose the often-severe health consequences of chronic diseases with the temporary side effects of dietary interventions.
Periodic assessments of other biomarkers—e.g., blood pressure, triglycerides, hemoglobin A1c, C-reactive protein, osmolality, apolipoprotein B, insulin—are also useful measures supporting safe implementation (64, 351). However, carnitine deficiency arising from a genetic defect, certain medications, or other health conditions may impede or prevent metabolic transition to nutritional ketosis (352). Additionally, individuals with rare inborn errors of metabolism involving gluconeogenesis, ketogenesis, or ketolysis would not be suited for using nutritional ketosis without medical supervision (353).
Micronutrients
It is important to recognize the role of micronutrients as cofactors in foods (354). Although both animal- and plant-based ketogenic diets can achieve low GKI values, diets comprised primarily of non-animal products may require additional supplementation, including (but not limited to) creatine, protein, zinc, vitamin B12, vitamin D, calcium, omega-3/omega-6 fatty acids, and other micronutrients (355, 356). Exogenous ketones exert marked benefits in acute settings, i.e., bridging the gap between carbohydrate depletion and endogenous ketone production (330, 357, 358). Nutritional literacy is essential for the successful implementation of a sustainable GKI (359, 360). Endogenous nutritional ketosis should therefore remain the basis for long-term adherence.
Physical activity
Physical activity can also lower an individual’s GKI. Both cardiovascular and weight-training exercise improve glucose homeostasis (361). Increased lean muscle mass augments glucose disposal at rest and during exercise (362, 363). βHB improves the work output of cardiac and skeletal muscle compared with the effect of glucose alone (287, 288). However, human studies have reported mixed results (364, 365). Ketogenic adaptation can be a significant factor when considering fatigue or recovery metrics (366). Nonetheless, athletes in nutritional ketosis often perform at similar or even better levels than in control groups (367, 368).
Managing psychological stress
Chronic psychological stress can exert significant adverse metabolic effects on the body (369). Stress-induced cortisol spikes contribute to chronic inflammation, increasing the risk for chronic disease and metabolic syndrome (370). Chronic stress also often leads to dietary over-consumption of hyperpalatable foods and weight gain (369). Consequently, stress reduction becomes yet another therapeutic strategy for improving metabolic health, despite the difficulty in quantification and assessment at the clinical level (, 371).
Synergy with the standards of care
When nutritional ketosis is indicated for the management of cancer and chronic diseases, it should be used in combination with existing treatments with a goal of synergistic effects (, 58, 59, 372–380). For example, a low GKI combined with chemotherapy and radiotherapy significantly extended the overall survival of some patients with brain cancer (60, 69). Nutritional ketosis improved psychiatric rating evaluations, metabolic biomarkers, life satisfaction, and sleep quality in patients with SCZ or BD who were taking psychotropic medications (57). Similarly, a modified ketogenic diet improved daily function, quality of life, and body weight in patients with AD (381). Lastly, a ketogenic diet reduced medication use, body weight, fasting insulin, and triglycerides in patients with T2D (382, 383). Importantly, the safety and feasibility profile of nutritional ketosis has been evaluated and confirmed in numerous studies (, , 384–389). Critically, while most of the evidence presented was drawn from relatively small clinical cohorts, we propose that the readily accessible GKI biomarker could allow larger interventional and observational studies, support real-world adoption, and help correlate time spent in different GKI ranges with the effectiveness of prevention or management strategies across several chronic diseases.
We anticipate that the use of nutritional ketosis will also allow for active patient engagement during conventional treatment, potentially improving both patient satisfaction and outcomes (390, 391). Patient engagement empowers individuals to take an active role in the management of their conditions at home, rather than relying on pharmaceutical interventions alone (391). The GKI zones can be used as a roadmap for both patients and clinicians to monitor nutritional adherence (Figure 5). Patients may be able to better self-evaluate their degree of ketosis by stratifying their position across zones. Moreover, because GKI is expressed as a single ratio, it may be more comparable across patient populations than basal plasma glucose alone, which can vary significantly between individuals. Hence, the GKI can serve as a quantitative biomarker for maintaining biologically defined adherence in both outpatient (in-home and telehealth) and clinical settings.
A GKI research roadmap
This is a rapidly developing field with an increasing number of clinical trials and case reports evaluating the use of nutritional ketosis in combination with conventional therapies for preventing or managing cancer, T2D, psychiatric disorders, obesity, and other chronic diseases. However, discrepancies in evaluating nutritional ketosis make comparing data between cohorts difficult. Thus, we propose standardizing this practice by calling for weekly, or ideally daily, reporting of plasma glucose, plasma ketones, and GKI values whenever ketosis is assessed in the clinic. Previous studies often report infrequent βHB or GKI values. The ideal time to measure GKI is at 2 h post-prandially in the evening or 2 h post-prandially in the morning; however, measurements in the morning can be conflated by overnight fasting.
We consider a βHB value of 0.5 mM as the baseline for nutritional ketosis. While implementation of dietary interventions can be challenging in randomized cohorts, greater emphasis should be placed on practical reasons for low endogenous ketogenesis, some of which may include lenient food choices, inadequate educational material, temporary side effects, patient motivation, habituation to previous food habits, eating disorders (e.g., binge eating), food addiction, and social pressure (392). Strict long-term adherence remains a roadblock for larger clinical adoption. In this review, we focused on establishing flexible GKI ranges over time as a practical tool to navigate such limitations, with the understanding that adherence may fluctuate over time (especially in primary prevention), whereas management of active chronic diseases may require a more stringent implementation to match the severity of the treated condition.
The efficacy of nutritional ketosis should be evaluated in studies that report high adherence and degree of ketosis, and ketosis should ideally be evaluated by GKI values. For example, an individual with 5.5-mM glucose and 0.3-mM ketones readings has a GKI of 18, whereas an individual with 5.0-mM glucose and 0.5-mM ketones readings has a GKI of 10. The absolute change in glucose or ketones alone may not appear significant, yet when taken as a ratio and averaged over time, this may signal a more significant change in adherence and biological effects through insulin suppression. Recent studies in patients with brain cancers show that the GKI measurement was better at assessing nutritional ketosis than were measurements of glucose or ketone levels alone (329). This relationship was also recently shown in 10 patients with high-grade glioma (69). Continued clinical research is required to verify efficacy across heterogeneous patient cohorts, including diverse socioeconomic and cultural contexts, as well as to minimize unexpected interactions between nutritional ketosis and other therapies currently used in the clinic.
Future studies utilizing the GKI should also evaluate other blood biomarkers. A low GKI is the result of stable, euglycemic plasma glucose and elevated βHB production; however, the index does not consider other metabolic benefits. For example, a low GKI value may also correlate with changes in other biomarkers, including low levels of triglycerides, inflammatory markers, and insulin (). Dual reporting of standard biomarkers alongside the GKI will provide insight into possible mechanisms behind improved health outcomes.
Finally, disease-specific GKI zones will be elucidated once ample clinical data are available. Identifying the precise combinations of benefit, adherence, and time required will allow for more comprehensive GKI zones for individual diseases. Clear and tangible roadmaps will become invaluable for both patient education and patient motivation. Together, more comprehensive reporting and clinical data will help validate the GKI as a reliable tool for widespread use both at home and in the clinic.
Conclusion
Mitochondrial dysfunction is implicated in many chronic diseases and cancer. Inefficient or insufficient energy production through oxidative respiration contributes to the deleterious downstream phenomena occurring in cancer and in other chronic diseases. A quantitative scale of GKI values linked to color-coded zones of health may provide a cohesive readout beyond weight loss for monitoring adherence and metabolic status. Low GKI values reflect metabolic conditions associated with improved mitochondrial function and may predict lower disease risk, whereas high GKI values are associated with mitochondrial dysfunction and may predict higher disease risk. The GKI, used together with science-based nutrition and exercise, may serve as a biomarker to support therapeutic strategies aimed at improving mitochondrial health across various cancers and chronic diseases regardless of age, sex, or genetic predisposition. As such, its evaluation and use via the roadmap we present may contribute to efforts to curb the epidemic of cancer and chronic diseases.
Statements
Data availability statement
The original contributions presented in this work are included in the article. Further inquiries can be directed to the corresponding authors.
Author contributions
DCL: Conceptualization, Visualization, Writing – original draft, Writing – review & editing.
TD: Conceptualization, Writing – review & editing.
IDC: Writing – review & editing.
JCM: Writing – review & editing.
KS: Writing – review & editing.
WA-H: Writing – review & editing.
EO: Writing – review & editing.
AEE: Writing – review & editing.
TNS: Conceptualization, Funding acquisition, Supervision, Writing – review & editing.
Funding
The authors declared that financial support was received for this work and/or its publication. TNS received support for this study via the Foundation for Metabolic Cancer Therapies, Dr. Edward Miller, Ezzio Partesano, Iren Vitanova, The Broken Science Initiative, Children with Cancer UK (grant no. 19-313), The Robert L. Corkin Charitable Foundation, The Elizabeth Ann Weathers Breast Cancer Research Fund, and the Boston College Research Expense Fund. JCM received support for this study from the Nelson and Claudia Peltz Foundation. The funders were not involved in the writing, editing, or conceptualization of this manuscript or the decision to submit it for publication.
Conflict of interest
The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The handling editor ACS declared a past co-authorship with the authors.
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The authors declared that generative AI was not used in the creation of this manuscript.
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Summary
Keywords
cancer, chronic disease, glucose ketone index, ketones, mitochondria, oxidative phosphorylation, reactive oxygen species, β-hydroxybutyrate
Citation
Lee DC, Duraj T, Cooper ID, Maroon JC, Smith K, Abdel-Hadi W, Omene E, Evangeliou AE and Seyfried TN (2026) The glucose ketone index: a proposed quantitative biomarker to support cancer and chronic disease prevention and management. Front Sci 4:1763395. doi: 10.3389/fsci.2026.1763395
Received
08 December 2025
Revised
23 March 2026
Accepted
23 April 2026
Published
14 July 2026
Volume
4 - 2026
Edited by
Adrienne C Scheck, University of Arizona, United States
Reviewed by
Eric Westman, Duke University, United States
Daniel Raftery, University of Washington, United States
Updates
Copyright
© 2026 Lee, Duraj, Cooper, Maroon, Smith, Abdel-Hadi, Omene, Evangeliou and Seyfried.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Thomas N. Seyfried, thomas.seyfried@bc.edu; Derek C. Lee, leebig@bc.edu
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.