The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for metabolic management of brain cancer
© Meidenbauer et al.; licensee BioMed Central. 2015
Received: 19 November 2014
Accepted: 24 February 2015
Published: 11 March 2015
Metabolic therapy using ketogenic diets (KD) is emerging as an alternative or complementary approach to the current standard of care for brain cancer management. This therapeutic strategy targets the aerobic fermentation of glucose (Warburg effect), which is the common metabolic malady of most cancers including brain tumors. The KD targets tumor energy metabolism by lowering blood glucose and elevating blood ketones (β-hydroxybutyrate). Brain tumor cells, unlike normal brain cells, cannot use ketone bodies effectively for energy when glucose becomes limiting. Although plasma levels of glucose and ketone bodies have been used separately to predict the therapeutic success of metabolic therapy, daily glucose levels can fluctuate widely in brain cancer patients. This can create difficulty in linking changes in blood glucose and ketones to efficacy of metabolic therapy.
A program was developed (Glucose Ketone Index Calculator, GKIC) that tracks the ratio of blood glucose to ketones as a single value. We have termed this ratio the Glucose Ketone Index (GKI).
The GKIC was used to compute the GKI for data published on blood glucose and ketone levels in humans and mice with brain tumors. The results showed a clear relationship between the GKI and therapeutic efficacy using ketogenic diets and calorie restriction.
The GKIC is a simple tool that can help monitor the efficacy of metabolic therapy in preclinical animal models and in clinical trials for malignant brain cancer and possibly other cancers that express aerobic fermentation.
Dietary therapy using ketogenic diets is emerging as an alternative or complementary approach to the current standard of care for brain cancer management. Prognosis remains poor for malignant gliomas in both children and adults [1-5]. Although genetic heterogeneity is extensive in malignant gliomas [6-8], the Warburg effect (aerobic fermentation of glucose) is a common metabolic malady expressed in nearly all neoplastic cells of these and other malignant tumors [9-11]. Aerobic fermentation (Warburg effect) is necessary to compensate for the insufficiency of mitochondrial oxidative phosphorylation in the cells of most tumors [9,12-14]. Mitochondrial structure and function is abnormal in malignant gliomas from both mice and humans [15-19]. Normal brain cells gradually transition from the metabolism of glucose to the metabolism of ketone bodies (primarily β-hydroxybutyrate and acetoacetate) for energy when circulating glucose levels become limiting [20,21]. Ketone bodies are derived from fatty acids in the liver and are produced to compensate for glucose depletion during periods of food restriction . Ketone bodies bypass the glycolytic pathway in the cytoplasm and are metabolized directly to acetyl CoA in the mitochondria . Tumor cells are less capable than normal cells in metabolizing ketone bodies for energy due to their mitochondrial defects [2,12,23].
Low Glucose Ketone Index values are related to improved prognoses in humans and mice with brain tumors
# of subjects
Days on diet
Ketones f (mM)
Glucose Ketone Index
No response to standard chemotherapy
FDG uptake at tumor site was decreased by 21.77%; tumor margins were unchanged
Tumor resected and initiated on KD while under standard chemotherapy,after tumor was radiologically stable by CT
FDG uptake at tumor site was decreased by 21.84%
Notes: Both patients remained in remission after return to standard diet for 5 years (Subject 1) and 4 years (Subject 2),at time of publication
Incomplete surgical resection of tumor; received chemotherapy and radiation therapy concurrent with diet
No evidence of tumor by MRI after concurrent therapy
Notes: Patient stayed on low calorie diet for an additional 5 months; tumor recurrence 3 months after low-calorie diet suspension
Mouse CT-2A astrocytoma
Tumor dry weight:55 ± 15mgh
Syngenic (C57BL/6 J)
Tumor dry weight:7 ± 7 mg
Tumor dry weight:70 ± 15 mg
Tumor dry weight:14 ± 8 mg
Mouse CT-2A astrocytoma
Tumor dry weight:95 ± 25mgh
Syngenic (C57BL/6 J)
Tumor dry weight:90 ± 15 mg
Tumor dry weight:35 ± 5 mg
Human U87-MG glioma
Tumor dry weight:60 ± 10mgh
Tumor dry weight:60 ± 7 mg
Tumor dry weight:37 ± 5 mg
Mouse GL261 glioma
Median survival time:23 days
Median survival time:28 days
SD-UR + Rade
Median survival time:41 days
KD-UR + Rad
Median survival time:200 + days
The second clinical study evaluated a 65-yr-old woman with glioblastoma multiforme . The patient was placed on a calorie-restricted ketogenic diet (600 kcal/day) concomitant with standard chemotherapy and radiation, without dexamethasone, for eight weeks. The patient’s GKI decreased from 37.5 to 1.4 in the first three weeks of the diet. No discernible brain tumor tissue was detected with MRI in the patient at the end of eight weeks of the calorie restricted ketogenic diet. It is also important to mention that the patient was free of symptoms while she adhered to the KD. Tumor recurrence occurred 10 weeks after suspension of the ketogenic diet.
The third study, a preclinical mouse study, evaluated the effects of diets on an orthotopically implanted CT-2A syngeneic mouse astrocytoma in C57BL/6 J mice . Mice were implanted with tumors and fed one of four diets for 13 days: 1) standard diet fed unrestricted, 2) calorie restricted standard diet, 3) ketogenic diet fed unrestricted, or 4) calorie restricted ketogenic diet. The mice fed a standard unrestricted diet and a ketogenic diet had rapid tumor growth after 13 days, and a GKI of 15.2 and 11.4, respectively. The group fed a calorie restricted standard diet had a significant decrease in tumor volume after 13 days, along with a GKI of 3.7. The group fed a calorie restricted ketogenic diet also had a significant decrease in tumor volume, along with a GKI of 4.4.
The fourth study evaluated the effects of diets on an orthotopically implanted CT-2A syngeneic mouse astrocytoma in C57BL/6 J mice and an orthotopically implanted human U87-MG human xenograft glioma in BALBc/6-severe combined immunodeficiency (SCID) mice . Tumors were implanted and grown in the mice for three days prior to diet initiation. After three days, mice were maintained on one of three diets for 8 days: 1) standard diet fed unrestricted, 2) ketogenic diet fed unrestricted, or 3) calorie restricted ketogenic diet. Tumor weights at the end of 8 days were reduced only in the mice that were fed a calorie restricted diet and experienced a significant decrease in GKI. Groups of mice that did not have a reduction in tumor weight had GKI’s that ranged from 9.6 – 70.0. The groups of mice that had a reduction in tumor weight had GKI’s that ranged from 1.8 – 4.4.
The fifth study evaluated the effects of diet and radiation on mouse GL261 glioma implanted intracranially in albino C57BL/6 J mice . The mice were implanted with tumors, and three days later they were placed on either a standard diet fed unrestricted or a ketogenic diet fed unrestricted. Mice were also assigned to groups that either received or did not receive concomitant radiation therapy. Without radiation, mice that were fed a ketogenic diet had a GKI of 6.4 and had a median survival of 28 days, compared to a GKI of 50.0 and median survival of 23 days for the standard diet group. With radiation, mice that were fed a ketogenic diet had a GKI of 5.7 and a median survival of 200+ days, compared to a GKI of 32.3 and median survival of 41 days for the standard diet group.
Linking the Glucose Ketone Index (GKI) to the therapeutic action of calorie restriction against distal invasion, proliferation, and angiogenesis in the VM-M3 model of glioblastoma
Distal invasion (photons/sec)
Proliferation (Ki67 %)
11.2 ± 0.6
0.7 ± 0.09
15.3 ± 0.9
14 ± 1.8
48 ± 1.2
15 ± 1.1
8.3 ± 0.8
1.32 ± 0.1
6.5 ± 0.9
6 ± 0.9
34 ± 1.5
7 ± 0.72
We present evidence showing that the GKI can predict success for brain cancer management in humans and mice using metabolic therapies that lower blood glucose and elevate blood ketone levels. Besides ketogenic diets, other dietary therapies, such as calorie restriction, low carbohydrate diets, and therapeutic fasting, can also lower blood glucose and elevate β-OHB levels and can have anti-tumor effects [24,33-38]. The GKIC was developed to more reliably and simply predict therapeutic management for brain cancer patients under these dietary states than could measurements of either blood glucose or ketones alone. The data presented in Tables 1 and 2 support this prediction. Although the GKI is simple in concept, it has not been used previously to gage success of various metabolic therapies based on inverse changes in glucose and ketone body metabolism.
As brain tumor cells are dependent on glucose for survival and cannot effectively use ketone bodies as an alternative fuel, a zone of metabolic management can be achieved under conditions of low glucose and elevated ketones. Ketone bodies also prevent neurological symptoms associated with hypoglycemia, such as neuroglycopenia, which allows blood glucose levels to be lowered even further [22,39]. Hence, ketone body metabolism can protect normal brain cells under conditions that target tumor cells . The zone of metabolic management is considered the therapeutic state that places maximal metabolic stress on tumor cells while protecting the health and vitality of normal cells . We have presented substantial data showing that the GKI is validated in several studies in mice. We feel that prospective validation of the GKIC will be obtained from future studies using ketogenic diet therapy in humans with brain cancer and possibly other cancers that cannot effectively metabolize β-OHB for energy, and depend upon glucose for survival.
The GKI can be useful in determining the success of dietary therapies that shift glucose- and lactate-based metabolism to ketone-based metabolism. As a shift toward ketone-based metabolism underscores the utility of many dietary therapies in treating metabolic diseases [41,42], the GKI can be used in determining the therapeutic success of shifting metabolism in individual patients. The GKI therefore can be used to study the effectiveness of dietary therapy in clinical trials of patients under a range of dietary conditions, with a composite primary endpoint consisting of lowering the subjects’ GKI. This will allow investigators to parse the effects of successful dietary intervention on disease outcome from unsuccessful dietary intervention.
Recent clinical studies assessing the effects of dietary therapy on brain cancer progression have not measured both blood glucose and ketone bodies throughout the study periods [43,44]. Future clinical studies that intend to assess the effect of dietary therapy on brain tumor progression should measure both blood glucose and ketone, as these markers are necessary to connect dietary therapy to therapeutic efficacy. Preclinical studies have demonstrated a clear linkage between GKI and therapeutic efficacy. The GKI will be an important biomarker to measure in future rigorously designed and powered clinical studies in order to demonstrate if there is a linkage between GKI and therapeutic efficacy, as the few case reports in the literature suggest.
The zone of metabolic management is likely entered with GKI values between 1 and 2 for humans. Optimal management is predicted for values approaching 1.0, and blood glucose and ketone values should be measured 2–3 hours postprandial, twice a day if possible. This will allow individuals to connect their dietary intake to changes in their GKI. As an example, Figure 2 uses the GKIC to track the GKI values of an individual on a ketogenic diet, with a target GKI of 1.0. When an individual’s GKI falls below the line denoting the target metabolic state, the zone of metabolic management is achieved. Further studies will be needed to establish the validity of the predicted zone of management.
It has not escaped our attention that the GKIC could have utility not only for managing brain cancer and possibly other cancers dependent on glucose and aerobic fermentation for survival, but also for managing other diseases or conditions where the ratio of glucose to ketone bodies could be therapeutic. Such diseases and conditions include Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, chronic inflammatory disease, and epilepsy . For example, the ketogenic diet has long been recognized as an effective therapeutic strategy for managing refractory seizures in children [45,46]. Therapeutic success in managing generalized idiopathic epilepsy in epileptic EL mice can also be seen when applying the GKI to the data presented on glucose and β-OHB . Healthy individuals can utilize the GKIC to prevent diseases and disorder, and manage general wellness. Further studies will be needed to determine the utility of the GKIC for predicting therapeutic success in the metabolic management of disease.
This work was supported, in part, by the National Institutes of Health (HD-39722, NS-55195 and CA-102135), a grant from the American Institute of Cancer Research, and the Boston College Expense Fund (TNS). Authors would like to thank Madam Trudy Dupont for providing us with valuable data to develop the GKIC.
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