The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for metabolic management of brain cancer

Joshua J Meidenbauer, Purna Mukherjee, Thomas N Seyfried, Joshua J Meidenbauer, Purna Mukherjee, Thomas N Seyfried

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Keywords: Beta-hydroxybutyrate; Calorie restriction; Glioblastoma; Glucose; Ketogenic diet; Ketone bodies; Metabolic therapy; Warburg effect.

Figures

Figure 1
Figure 1
Relationship of plasma glucose and ketone body levels to brain cancer management. The glucose and ketone (β-­OHB) values are within normal physiological ranges under fasting conditions in humans. We refer to this state as the zone of metabolic management. As blood glucose falls and blood ketones rise, an individual is predicted to reach the zone of metabolic management. Tumor progression is predicted to be slower within the metabolic target zone than outside of the zone. This can be tracked utilizing the Glucose Ketone Index. The dashed lines signify the variability that could exist among individuals in reaching a GKI associated with therapeutic efficacy.
Figure 2
Figure 2
The Glucose Ketone Index Calculator tracking an individual’s GKI. The individual glucose and ketone values are displayed, along with the corresponding GKI values. The GKI values are plotted over the course of a month (black line), whereas the GKI target value (1.0) is plotted as a red line. We consider GKI values approaching 1.0 as potentially most therapeutic.

References

    1. Fisher PG, Buffler PA. Malignant gliomas in 2005: where to GO from here? JAMA. 2005;293:615–617. doi: 10.1001/jama.293.5.615.
    1. Seyfried TN, Marsh J, Mukherjee P, Zuccoli G, D’Agostino DP. Could metabolic therapy become a viable alternative to the standard of care for managing glioblastoma? US Neurology. 2014;10:48–55.
    1. Armstrong GT, Phillips PC, Rorke-Adams LB, Judkins AR, Localio AR, Fisher MJ. Gliomatosis cerebri: 20 years of experience at the Children’s Hospital of Philadelphia. Cancer. 2006;107:1597–1606. doi: 10.1002/cncr.22210.
    1. Artico M, Cervoni L, Celli P, Salvati M, Palma L. Supratentorial glioblastoma in children: a series of 27 surgically treated cases. Childs Nerv Syst. 1993;9:7–9. doi: 10.1007/BF00301926.
    1. Harbaugh KS, Black PM. Strategies in the surgical management of malignant gliomas. Semin Surg Oncol. 1998;14:26–33. doi: 10.1002/(SICI)1098-2388(199801/02)14:1<26::AID-SSU4>;2-4.
    1. Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014;343:189–193. doi: 10.1126/science.1239947.
    1. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462–477. doi: 10.1016/j.cell.2013.09.034.
    1. Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344:1396–1401. doi: 10.1126/science.1254257.
    1. Ferreira LM. Cancer metabolism: the Warburg effect today. Exp Mol Pathol. 2010;89:372–380. doi: 10.1016/j.yexmp.2010.08.006.
    1. Seyfried TN, Mukherjee P. Targeting energy metabolism in brain cancer: review and hypothesis. Nutr Metab (Lond) 2005;2:30. doi: 10.1186/1743-7075-2-30.
    1. Seyfried TN, Flores R, Poff AM, D'Agostino DP, Mukherjee P. Metabolic therapy: a new paradigm for managing malignant brain cancer. Cancer Lett. 2014;356:289–300. doi: 10.1016/j.canlet.2014.07.015.
    1. Seyfried TN, Flores RE, Poff AM, D’Agostino DP. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis. 2014;35:515–527. doi: 10.1093/carcin/bgt480.
    1. Warburg O. On the origin of cancer cells. Science. 1956;123:309–314. doi: 10.1126/science.123.3191.309.
    1. Warburg O. On the respiratory impairment in cancer cells. Science. 1956;124:269–270.
    1. Kiebish MA, Han X, Cheng H, Chuang JH, Seyfried TN. Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer. J Lipid Res. 2008;49:2545–2556. doi: 10.1194/jlr.M800319-JLR200.
    1. Arismendi-Morillo GJ, Castellano-Ramirez AV. Ultrastructural mitochondrial pathology in human astrocytic tumors: potentials implications pro-therapeutics strategies. J Electron Microsc (Tokyo) 2008;57:33–39. doi: 10.1093/jmicro/dfm038.
    1. Deighton RF, Le Bihan T, Martin SF, Gerth AM, McCulloch M, Edgar JM, et al. Interactions among mitochondrial proteins altered in glioblastoma. J Neurooncol. 2014;118:247–256. doi: 10.1007/s11060-014-1430-5.
    1. Oudard S, Boitier E, Miccoli L, Rousset S, Dutrillaux B, Poupon MF. Gliomas are driven by glycolysis: putative roles of hexokinase, oxidative phosphorylation and mitochondrial ultrastructure. Anticancer Res. 1997;17:1903–1911.
    1. Sipe JC, Herman MM, Rubinstein LJ. Electron microscopic observations on human glioblastomas and astrocytomas maintained in organ culture systems. Am J Pathol. 1973;73:589–606.
    1. Cahill GF, Jr, Veech RL. Ketoacids? Good medicine? Trans Am Clin Climatol Assoc. 2003;114:149–161.
    1. Krebs HA, Williamson DH, Bates MW, Page MA, Hawkins RA. The role of ketone bodies in caloric homeostasis. Adv Enzyme Reg. 1971;9:387–409. doi: 10.1016/S0065-2571(71)80055-9.
    1. Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF., Jr Ketone bodies, potential therapeutic uses. IUBMB Life. 2001;51:241–247. doi: 10.1080/152165401753311780.
    1. Fine EJ, Miller A, Quadros EV, Sequeira JM, Feinman RD. Acetoacetate reduces growth and ATP concentration in cancer cell lines which over-express uncoupling protein 2. Cancer Cell Int. 2009;9:14. doi: 10.1186/1475-2867-9-14.
    1. Klement RJ, Kammerer U. Is there a role for carbohydrate restriction in the treatment and prevention of cancer? Nutr Metab. 2011;8:75. doi: 10.1186/1743-7075-8-75.
    1. Seyfried TN, Kiebish M, Mukherjee P, Marsh J. Targeting energy metabolism in brain cancer with calorically restricted ketogenic diets. Epilepsia. 2008;49(Suppl 8):114–116. doi: 10.1111/j.1528-1167.2008.01853.x.
    1. Goetsch VL, Wiebe DJ, Veltum LG, Van Dorsten B. Stress and blood glucose in type II diabetes mellitus. Behav Res Ther. 1990;28:531–537. doi: 10.1016/0005-7967(90)90140-E.
    1. Nebeling LC, Miraldi F, Shurin SB, Lerner E. Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. J Am Coll Nutr. 1995;14:202–208. doi: 10.1080/07315724.1995.10718495.
    1. Zuccoli G, Marcello N, Pisanello A, Servadei F, Vaccaro S, Mukherjee P, et al. Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report. Nutr Metab (Lond) 2010;7:33. doi: 10.1186/1743-7075-7-33.
    1. Seyfried TN, Sanderson TM, El-Abbadi MM, McGowan R, Mukherjee P. Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. Br J Cancer. 2003;89:1375–1382. doi: 10.1038/sj.bjc.6601269.
    1. Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN. The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond) 2007;4:5. doi: 10.1186/1743-7075-4-5.
    1. Abdelwahab MG, Fenton KE, Preul MC, Rho JM, Lynch A, Stafford P, et al. The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. PLoS One. 2012;7:e36197. doi: 10.1371/journal.pone.0036197.
    1. Shelton LM, Huysentruyt LC, Mukherjee P, Seyfried TN. Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse. ASN Neuro. 2010;2:e00038. doi: 10.1042/AN20100002.
    1. Fine EJ, Segal-Isaacson CJ, Feinman RD, Herszkopf S, Romano MC, Tomuta N, et al. Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients. Nutrition. 2012;28:1028–1035. doi: 10.1016/j.nut.2012.05.001.
    1. Klement RJ. Calorie or carbohydrate restriction? The ketogenic diet as another option for supportive cancer treatment. Oncologist. 2013;18:1056. doi: 10.1634/theoncologist.2013-0032.
    1. Klement RJ, Champ CE. Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation. Cancer Metastasis Rev. 2014;33:217–229. doi: 10.1007/s10555-014-9495-3.
    1. Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014;19:181–192. doi: 10.1016/j.cmet.2013.12.008.
    1. Raffaghello L, Safdie F, Bianchi G, Dorff T, Fontana L, Longo VD. Fasting and differential chemotherapy protection in patients. Cell Cycle. 2010;9:4474–4476. doi: 10.4161/cc.9.22.13954.
    1. Woolf EC, Scheck AC. The ketogenic diet for the treatment of malignant glioma. J Lipid Res. 2015;56:5–10. doi: 10.1194/jlr.R046797.
    1. Willemsen MA, Soorani-Lunsing RJ, Pouwels E, Klepper J. Neuroglycopenia in normoglycaemic patients, and the potential benefit of ketosis. Diabet Med. 2003;20:481–482. doi: 10.1046/j.1464-5491.2003.00952.x.
    1. Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev. 2009;59:293–315. doi: 10.1016/j.brainresrev.2008.09.002.
    1. Seyfried TN. Ketone strong: emerging evidence for a therapeutic role of ketone bodies in neurological and neurodegenerative diseases. J Lipid Res. 2014;55:1815–17. doi: 10.1194/jlr.E052944.
    1. Meidenbauer JJ, Ta N, Seyfried TN. Influence of a ketogenic diet, fish-oil, and calorie restriction on plasma metabolites and lipids in C57BL/6 J mice. Nutr Metab. 2014;11:23. doi: 10.1186/1743-7075-11-23.
    1. Rieger J, Bahr O, Maurer GD, Hattingen E, Franz K, Brucker D, et al. ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. Int J Oncol. 2014;44:1843–1852.
    1. Champ CE, Palmer JD, Volek JS, Werner-Wasik M, Andrews DW, Evans JJ, et al. Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. J Neurooncol. 2014;117:125–131. doi: 10.1007/s11060-014-1362-0.
    1. Freeman JM, Kossoff EH. Ketosis and the ketogenic diet, 2010: advances in treating epilepsy and other disorders. Adv Pediatr. 2010;57:315–329. doi: 10.1016/j.yapd.2010.08.003.
    1. Hartman AL, Vining EP. Clinical aspects of the ketogenic diet. Epilepsia. 2007;48:31–42. doi: 10.1111/j.1528-1167.2007.00914.x.
    1. Mantis JG, Centeno NA, Todorova MT, McGowan R, Seyfried TN. Management of multifactorial idiopathic epilepsy in EL mice with caloric restriction and the ketogenic diet: role of glucose and ketone bodies. Nutr Metab (Lond) 2004;1:11. doi: 10.1186/1743-7075-1-11.

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