Glucose Ketone Index (GKI) and L-Glutamine Metabolism for Cancer Management

Press-Pulse Insights from Dr. Thomas Seyfried
Written by Keith Bishop, CN, B.Sc. Pharmacy, Author

November 27, 2023

This paper discusses the Glucose Ketone Index (GKI) a tool developed by Dr. Thomas Seyfried and his team at Boston College, and L-Glutamine restriction as a strategy for managing cancer growth.[1] The GKI It is the ratio of blood glucose to ketone bodies. The higher the ratio the higher the glucose and lower the ketone bodies. The lower the ratio the lower the glucose and higher the ketone bodies.

GKI and Cancer

There is a very strong association between elevated blood glucose, oxidative stress, inflammation and the higher risk of cancer.[2] Ketone bodies (the body using fat for energy) and ketogenic diets appear to be powerful agents in treating human cancers. Ketone bodies often enhance the effectiveness of chemotherapy treatments.[3]

Dr. Seyfried's research in the realm of cancer treatment has shown increasingly impressive therapeutic outcomes with lower GKI ratios¹ (lower blood glucose and higher ketone bodies). He claims that a GKI of less than 1.0 is prime therapy for patients with cancer¹. The GKI is one number that helps you determine your degree of ketosis.

Optimal GKI for Cancer Management

According to Dr. Seyfried, the optimal GKI range for cancer treatment and prevention is between 0.7-2.0, preferably around 1.0. This range is the most effective in preventing cancer cell growth⁵. At this range cancer cells have difficulty using glucose for energy while normal cells can easily adapt to ketone bodies for energy.

The KetoMojo fingerstick monitor is a convenient method of monitoring GKI.

GKI Numbers

Restricting L-Glutamine in Cancer Treatment

L-glutamine (glutamine) is an amino acid from protein. Most proteins have glutamine or amino acid precursors to glutamine. Our body requires glutamine to grow, repair, survive and multiply. Many cancer cells also use glutamine to grow, survive, and multiply — so much so that they can become dependent on it.[4] In fact, glutamine is believed to be such an important part of tumor progression that many researchers are studying restricting it as a potential cancer treatment.[5] It’s believed that normal body cells can adapt to lower levels of glutamine better than cancer cells. Restricting dietary glutamine is difficult and unhealthy so researchers are developing compounds to reduce the amount of glutamine the body can use or make from other amino acids.

DON (6-diazo-5-oxo-L-norleucine) is a prescription antagonist that blocks glutamine metabolism.[6] In theory, this compound and derivative could be used across a wide spectrum of cancer types. The challenge is finding a practitioner that is knowledgeable in prescribing and adjusting dosages based on patient response and side effects. Remember, normal cells must have glutamine so we can’t block it 100%.

Press – Pulse

The press-pulse therapeutic strategy for cancer management is illustrated with calorie restricted ketogenic diets (KD-R) of reduced glucose and increased ketones used together with drugs and procedures that create both chronic (press) and intermittent acute stress (pulse) on tumor cell energy metabolism, while protecting and enhancing the energy metabolism of normal cells.

I do several of the following Press-Pulse therapies to lower my familial risk of prostate cancer.

The Press

The press is putting stress on cancer cells all the time.

1. Intermittent Fasting
   Fasting lowers blood glucose and glutamine while increasing ketone bodies. I find most of my clients require 14+ hours of fasting from proteins and carbohydrates to get into a GKI of 1-3. Click here to learn more about Timed Eating for Cancer.
2. Low Glycemic Impact Foods
   During the eating time of 6-8 hours consuming foods with a low glycemic impact such as discussed in Cancer Food Tactics. I recommend using the Fitindex weight scale and smart phone app to make sure a person is maintaining muscle and bone while losing or maintaining appropriate amounts of body fat.

Cancer cells often adapt to one therapy. Research is focusing on cutting off cellular energy by limiting glucose and L-Glutamine metabolism via several mechanisms.[7]

Supplements that can lower cancer cell glucose metabolism include:

• Berberine[8]
• Cannabidiol[9]
• Curcumin[10]
• Quercetin[11]
• EGCG[12]
• Resveratrol[13]
• Beta Glucan[14]
• Silymarin[15]
• Vitamin D3[16]
• Zinc[17]

Drugs that can lower glucose metabolism and use include:

• Fenbendazole[18]
• Ivermectin[19]
• Diabetes prescription drugs including metformin[20]

Herbs that can lower L-glutamine metabolism and use include:

• EGCG (epigallocatechin gallate) from green tea via glutamate dehydrogenase[21]
• Quercetin via glutamate dehydrogenase[22]
• Curcumin via blocking attachment of glutamine to cancer cells[23]
• Berberine by blocking transport of glutamine into cancer cells[24]
• Resveratrol via glutamine absorption[25]

The Pulse

The Pulse putting severe stress on the cancer cells for short periods of time. Examples include:

• Exercise
• Infrared Sauna
• Chemotherapy
• Radiation
• Repurposed drugs

Conclusion

The GKI, as proposed by Dr. Seyfried, presents a promising approach to cancer management. By maintaining a GKI of less than 1.0, it may be possible to inhibit cancer cell growth. However, more research is needed to fully understand and optimize this approach.

I often use the supplements found in the Flourish Store 

Notice

This information is based on research that is intended for educational purposes and should not be taken as medical advice. Always consult with your healthcare provider before making changes to your health regimen. Supplement statements have not been evaluated by the Food and Drug Administration. These supplements are not intended to diagnose, treat, cure, or prevent any disease.

Reference Sources Include

[1] https://s3.amazonaws.com/kajabi-storefronts-production/file-uploads/sites/2147693653/themes/2154085206/downloads/8a6b534-d120-c4a8-6fc5-36ae3ae32cfc_Press-pulse-metabolic-mitochondrial-management-of-cancer-Seyfried.pdf

[2] Shahraki S, Bahraini F, Mesbahzadeh B, Sayadi M, Sajjadi SM. Glucose increases proliferation and chemoresistance in chronic myeloid leukemia via decreasing antioxidant Properties of ω-3 polyunsaturated fatty acids in the presence of Iron. Mol Biol Rep. 2023;50(12):10315-10324. doi:10.1007/s11033-023-08891-7

[3] Miller AI, Diaz D, Lin B, et al. Ketone Bodies Induce Unique Inhibition of Tumor Cell Proliferation and Enhance the Efficacy of Anti-Cancer Agents. Biomedicines. 2023;11(9):2515. Published 2023 Sep 12. doi:10.3390/biomedicines11092515

[4] Xu F, Jiang HL, Feng WW, Fu C, Zhou JC. Characteristics of amino acid metabolism in colorectal cancer. World J Clin Cases. 2023;11(27):6318-6326. doi:10.12998/wjcc.v11.i27.6318

[5] Encarnación-Rosado J, Sohn ASW, Biancur DE, et al. Targeting pancreatic cancer metabolic dependencies through glutamine antagonism. Nat Cancer. Published online October 9, 2023. doi:10.1038/s43018-023-00647-3

[6] Encarnación-Rosado J, Sohn ASW, Biancur DE, et al. Targeting pancreatic cancer metabolic dependencies through glutamine antagonism. Nat Cancer. Published online October 9, 2023. doi:10.1038/s43018-023-00647-3

[7] Zhang K, Zhu J, Wang R, et al. Mitochondria-anchoring self-assembled nanoparticles for multi-path energy depletion: A "nano bomb" in chemo-co-starvation therapy. Int J Pharm. 2023;642:123180. doi:10.1016/j.ijpharm.2023.123180

[8] Yan SH, Hu LM, Hao XH, et al. Chemoproteomics reveals berberine directly binds to PKM2 to inhibit the progression of colorectal cancer. iScience. 2022;25(8):104773. Published 2022 Jul 20. doi:10.1016/j.isci.2022.104773

[9] Sun D, Li X, Nie S, Liu J, Wang S. Disorders of cancer metabolism: The therapeutic potential of cannabinoids. Biomed Pharmacother. 2023;157:113993. doi:10.1016/j.biopha.2022.113993

[10] Li Z, Gao Y, Li L, Xie S. Curcumin Inhibits Papillary Thyroid Cancer Cell Proliferation by Regulating lncRNA LINC00691. Anal Cell Pathol (Amst). 2022;2022:5946670. Published 2022 Feb 26. doi:10.1155/2022/5946670

[11] Hu M, Song HY, Chen L. Quercetin acts via the G3BP1/YWHAZ axis to inhibit glycolysis and proliferation in oral squamous cell carcinoma. Toxicol Mech Methods. 2023;33(2):141-150. doi:10.1080/15376516.2022.2103480

[12] Zhou Y, Huang S, Guo Y, et al. Epigallocatechin gallate circumvents drug-induced resistance in non-small-cell lung cancer by modulating glucose metabolism and AMPK/AKT/MAPK axis. Phytother Res. Published online August 24, 2023. doi:10.1002/ptr.7990

[13] Vidoni C, Ferraresi A, Vallino L, et al. Glycolysis Inhibition of Autophagy Drives Malignancy in Ovarian Cancer: Exacerbation by IL-6 and Attenuation by Resveratrol. Int J Mol Sci. 2023;24(2):1723. Published 2023 Jan 15. doi:10.3390/ijms24021723

[14] da Silva TP, Geraldelli D, Martins KO, et al. Antioxidant, anti-inflammatory and beneficial metabolic effects of botryosphaeran [(1→3)(1→6)-β-d-glucan] are responsible for its anti-tumour activity in experimental non-obese and obese rats bearing Walker-256 tumours. Cell Biochem Funct. Published online February 28, 2022. doi:10.1002/cbf.3690

[15] Sellam LS, Zappasodi R, Chettibi F, et al. Silibinin down-regulates PD-L1 expression in nasopharyngeal carcinoma by interfering with tumor cell glycolytic metabolism. Arch Biochem Biophys. 2020;690:108479. doi:10.1016/j.abb.2020.108479

[16] Xu Y, Hino C, Baylink DJ, et al. Vitamin D activates FBP1 to block the Warburg effect and modulate blast metabolism in acute myeloid leukemia [published correction appears in Biomark Res. 2022 May 19;10(1):33]. Biomark Res. 2022;10(1):16. Published 2022 Apr 2. doi:10.1186/s40364-022-00367-3

[17] Nazari M, Nikbaf-Shandiz M, Pashayee-Khamene F, et al. Zinc Supplementation in Individuals with Prediabetes and type 2 Diabetes: a GRADE-Assessed Systematic Review and Dose-Response Meta-analysis. Biol Trace Elem Res. Published online October 23, 2023. doi:10.1007/s12011-023-03895-7

[18] Dogra N, Kumar A, Mukhopadhyay T. Fenbendazole acts as a moderate microtubule destabilizing agent and causes cancer cell death by modulating multiple cellular pathways. Sci Rep. 2018;8(1):11926. Published 2018 Aug 9. doi:10.1038/s41598-018-30158-6

[19] Feng Y, Wang J, Cai B, Bai X, Zhu Y. Ivermectin accelerates autophagic death of glioma cells by inhibiting glycolysis through blocking GLUT4 mediated JAK/STAT signaling pathway activation. Environ Toxicol. 2022;37(4):754-764. doi:10.1002/tox.23440

[20] Ouyang J, Feng Y, Zhang Y, et al. Integration of metabolomics and transcriptomics reveals metformin suppresses thyroid cancer progression via inhibiting glycolysis and restraining DNA replication. Biomed Pharmacother. 2023;168:115659. doi:10.1016/j.biopha.2023.115659

[21] Sbirkov Y, Vergov B, Dzharov V, Schenk T, Petrie K, Sarafian V. Targeting Glutaminolysis Shows Efficacy in Both Prednisolone-Sensitive and in Metabolically Rewired Prednisolone-Resistant B-Cell Childhood Acute Lymphoblastic Leukaemia Cells. Int J Mol Sci. 2023;24(4):3378. Published 2023 Feb 8. doi:10.3390/ijms24043378

[22] Marsico M, Santarsiero A, Pappalardo I, et al. Mitochondria-Mediated Apoptosis of HCC Cells Triggered by Knockdown of Glutamate Dehydrogenase 1: Perspective for Its Inhibition through Quercetin and Permethylated Anigopreissin A. Biomedicines. 2021;9(11):1664. Published 2021 Nov 11. doi:10.3390/biomedicines9111664

[23] Huang YT, Lin YW, Chiu HM, Chiang BH. Curcumin Induces Apoptosis of Colorectal Cancer Stem Cells by Coupling with CD44 Marker. J Agric Food Chem. 2016;64(11):2247-2253. doi:10.1021/acs.jafc.5b05649

[24] Zhang P, Wang Q, Lin Z, Yang P, Dou K, Zhang R. Berberine Inhibits Growth of Liver Cancer Cells by Suppressing Glutamine Uptake. Onco Targets Ther. 2019;12:11751-11763. Published 2019 Dec 31. doi:10.2147/OTT.S235667

[25] Liu Z, Peng Q, Li Y, Gao Y. Resveratrol enhances cisplatin-induced apoptosis in human hepatoma cells via glutamine metabolism inhibition. BMB Rep. 2018;51(9):474-479. doi:10.5483/BMBRep.2018.51.9.114