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Sample submission for the Carnivore Conference

This was my original submission for AHS18. (See https://youtu.be/q-II2vBGn8U for the talk, and https://jevohealth.com/journal/vol3/iss1/11/ for the paper that came out of this work.)

This submission demonstrates the level of detail that an extended abstract can provide to allow the committee to see what your talk will entail. If there is any doubt, this can reassure the committee that you've thought it through, and give a flavour of the quality you will provide. This is especially helpful if you haven't given a talk before, or if the subject is unfamiliar.

The Carnivore Conference, like AHS, does not require an extended abstract, but if well written, it can give you an advantage.

Inuit Ketosis and the Arctic Variant of CPT1A: data, mechanisms, and evolutionary implications

Abstract

Inuit peoples are among the many cultures with a traditional diet of predominantly animal sourced foods and negligible carbohydrate. One might expect, then, that they would have been in ketosis most of the time. Some historical evidence suggests otherwise, leading to intense debate. Because the Inuit have been treated as an archetype and historical precedent for nutritional ketosis, stakes in this outcome appear high. If even the Inuit were not in ketosis, it seems that adopting a long-term, ketogenic lifestyle may be misguided, perhaps even dangerous. In this talk, I will present existing literature reporting ketosis measurements in Inuit populations, and explain why they are difficult to interpret. I will delve into research on the CPT1A Arctic variant, its effects on fat metabolism, and its potential selective advantages. Finally I will discuss the relevance of these observations in the broader context of ketosis and historical human diets.

Learning Objectives:

Upon completion of the session, participants will understand:

  1. How dietary confounders and technological limitations complicate historical measurements of ketosis in Inuit people
  2. Why the geographical localisation of the Arctic variant both limits the scope of its relevance and points to a selective pressure other than a genetic push against ketosis
  3. How one function of the arctic variant of CPT1A supports a ketosis-favourable interpretation of the gene.

Extended abstract:

In this talk I will examine the question of whether Inuit peoples are genetically predisposed to avoid ketosis, and what we can conclude about the ketogenic state based on the answer. I will provide evidence for and against the claim, both from historical documents with measurements, and from genetic studies.

For the historical documents, I will draw attention to the reported diets of the subjects, the tools used, the differences between measurements in fasting vs. fed, and the role of keto-adaptation. We will see how the limited measurements we have have been variously affected by carbohydrate intake from western food, reflected in the reports, and tools that can detect only the ketosis of fasting or ketosis in the early stages of keto-adaptation. These issues render the results inconclusive. Moreover, the publications include reports of Inuit people in at least mild ketosis when fasted rather than fed, which directly contradicts the claim that they are incapable of ketogenesis.

In light of this, we consider two alternative, more specific claims. The first is that Inuit are capable of ketosis when fasting, but their native diets are not ketogenic. With the measurement limitations already in mind, there is little to support or refute this. We do have a plausible mechanism for reduced ketosis of higher protein intake than is generally considered ketogenic. Thus the hypothesis cannot yet be ruled out. The second is that the inability to attain ketosis is limited to those with the specific Arctic variant of CPT1A.

In discussing the genetic variant, we'll first look at the localisation of the gene to a specific coastal, Arctic environment, and consider what the differences in selective pressure might have been. I'll discuss how one of the known effects of the variant drastically reduces the activity of the CPT1A enzyme, thereby reducing the ability of the liver to generate ketone bodies out of long chain fatty acids. Given that high intake of polyunsaturated fatty acids upregulates CPT1A, I'll suggest that this is exactly the relevant environmental difference separating the presence or absence of the mutation, and that it's possible that this increase compensates for the reduced activity from the variant. If so, this suggests two potential selective advantages of the gene: one is that it reduces possibly undesirable high levels of ketosis. The other is that it merely allows some other effect of the gene to be selected for, by eliminating the otherwise detrimental lowering of ketosis.

The other known effect of the Arctic variant is that it reduces the sensitivity of CPT1A to inhibition in the condition of higher glucose oxidation. This means that if ketosis is established, it will tend to continue at rates of glucose oxidation that would otherwise shift metabolism out of ketosis. One theory proposed by some scientists is that the advantage of this is to avoid the stress of keto-adaption after forays into higher carbohydrate levels in times of scarcity. A refinement to this theory might be that since higher protein levels would also be a potential source of higher glucose oxidation, the variant may exert advantage by allowing higher protein intake without compromisng ketosis.

This mechanism of robust ketosis has the added potential to explain other observations. Incidents of children with the variant being hospitalised with hypoketotic hypoglycemia after a short period without food suggest that the gene is dangerous. If the coastal regions had any regularity of food scarcity, which at least one paper suggests they did, it is hard to imagine how it could have survived. If the variant impairs fasting only when starting from a non-ketotic state, and the ketosis of fasting is unimpaired when initiated from a ketogenic state, there would be less to explain. This would also account for the above-mentioned evidence of mild fasting ketosis in Inuit, given that the subjects were from regions known to have high prevalence of the gene. This is an empirical question to which I have not yet found an answer.

Finally, I will discuss the implications of the findings. The sum of the data I have found is consistent with two different hypotheses. On one end of the spectrum, it could be that Inuit with and without the variant are keto-adapted and in mild ketosis normally when fed their traditional diets. The measurements were false negatives, and the hypoketotic hypoglycemia in fasting children is a result of a high carbohydrate diet. Under this hypothesis, regular, long-term, mild ketosis is the natural consequence of a diet low in carbohydrate, and in the coastal case also high in polyunsaturated fatty acids. The Inuit exemplify this nutritional paradigm.

Alternatively, it could be that those without the variant have diets that are too high in protein to be ketogenic normally, and that those with the variant do not get into ketosis even on a traditional coastal diet. This would support the notion that long-term ketosis is unhealthy, and its detriment was the factor that led to either a traditional diet that prevents ketosis or a genetic push away from ketosis when the diet did not. Further experiments in people with and without the variant may help distinguish these hypotheses. As it stands it is an open question.

References:

Measurements of Diet and Metabolism in Inuit

Krogh A, Krogh M. A Study of the Diet and Metabolism of Eskimos Undertaken in 1908 on an Expedition to Greenland. https://archive.org/details/meddelelseromgr511915denm

Heinbecker, Peter. Studies on the Metabolism of Eskimos J. Biol. Chem. 1928 80: 461-. http://www.jbc.org/content/80/2/461.short

Heinbecker, Peter. Further Studies on the Metabolism of Eskimos J. Biol. Chem. 1931 93: 327-. http://www.jbc.org/content/93/2/327.full.pdf+html

Ho, Kang-Jey, Belma Mikkelson, Lena A. Lewis, Sheldon A. Feldman, and C. Bruce Taylor. “Alaskan Arctic Eskimo: Responses to a Customary High Fat Diet.” The American Journal of Clinical Nutrition 25, no. 8 (August 1, 1972): 737–45. https://doi.org/10.1093/ajcn/25.8.737.

Feldman, S. A., A. H. Rubenstein, null Ho K-J, C. B. Taylor, L. A. Lewis, and B. Mikkelson. “Carbohydrate and Lipid Metabolism in the Alaskan Arctic Eskimo.” The American Journal of Clinical Nutrition 28, no. 6 (June 1975): 588–94. https://www.ncbi.nlm.nih.gov/pubmed/1130318

Sensitivity of measuring ketosis by acetoacetate

Bradley G. M., and E. S. Benson. Examination of the urine. In: Todd-Sanford: Clinical Diagnosis by Laboratory Methods (14th ed.), edited by I. Davidsohn and J. B. Henry. Philadelphia: Saunders, 1969, chapt. 3, p. 65 https://archive.org/stream/in.ernet.dli.2015.146248/2015.146248.Todd-sanford-Clinical-Diagnosis-Fourteenth-Edition_djvu.txt

Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Walker HK, Hall WD, Hurst JW, editors. Boston: Butterworths; 1990. http://www.ncbi.nlm.nih.gov/books/NBK247/

Medical Laboratory Science : Theory And Practice Ochei Et Al. Tata McGraw-Hill Education, Aug 1, 2000. p 134 http://books.google.com/books?id=lciNs3VQPLoC

Blackwell's Five-Minute Veterinary Consult: Laboratory Tests and Diagnostic Procedures Shelly L. Vaden, Joyce S. Knoll, Francis W. K. Smith, Jr., Larry P. Tilley John Wiley & Sons, Jun 13, 2011 http://books.google.com/books?id=htie9uqN19wC

Acetoacetate Levels Differ Before and After Keto-adaptation Affecting Detection

Comparative measurements of glucose, beta-hydroxybutyrate, acetoacetate, and insulin in blood and cerebrospinal fluid during starvation. Owen OE, Reichard GA Jr, Boden G, Shuman C. Metabolism. 1974 Jan;23(1):7-14. http://www.sciencedirect.com/science/article/pii/0026049574900985

A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Neal EG1, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. Epilepsia. 2009 May;50(5):1109-17. doi: 10.1111/j.1528-1167.2008.01870.x. Epub 2008 Nov 19. http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2008.01870.x/full

The Art and Science of Low Carbohydrate Living: An Expert Guide to Making the Life-Saving Benefits of Carbohydrate Restriction Sustainable and Enjoyable Jeff Volek and Steven Phinney Publisher: Beyond Obesity LLC; 1St Edition edition (May 19, 2011)

Prevalence and Geography of the CPT1A variant

Collins, Sorcha A., Graham Sinclair, Sarah McIntosh, Fiona Bamforth, Robert Thompson, Isaac Sobol, Geraldine Osborne, et al. “Carnitine Palmitoyltransferase 1A (CPT1A) P479L Prevalence in Live Newborns in Yukon, Northwest Territories, and Nunavut.” Molecular Genetics and Metabolism 101, no. 2–3 (October 2010): 200–204. https://doi.org/10.1016/j.ymgme.2010.07.013.

Clemente, Florian J., Alexia Cardona, Charlotte E. Inchley, Benjamin M. Peter, Guy Jacobs, Luca Pagani, Daniel J. Lawson, et al. “A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations.” The American Journal of Human Genetics 95, no. 5 (November 6, 2014): 584–89. https://doi.org/10.1016/j.ajhg.2014.09.016.

Hirshfield, Matthew. Slide presentation, date uncertain. “Arctic-Variant-CPT-1.Pdf.” https://yk-health.org/images/3/36/Arctic-Variant-CPT-1.pdf.

Effects of CPT1A sensitivity to Malonyl-CoA

Ontko, J. A., and M. L. Johns. “Evaluation of Malonyl-CoA in the Regulation of Long-Chain Fatty Acid Oxidation in the Liver. Evidence for an Unidentified Regulatory Component of the System.” Biochemical Journal 192, no. 3 (December 15, 1980): 959–62. https://doi.org/10.1042/bj1920959.

Bremer, J. “The Effect of Fasting on the Activity of Liver Carnitine Palmitoyltransferase and Its Inhibition by Malonyl-CoA.” Biochimica Et Biophysica Acta 665, no. 3 (September 24, 1981): 628–31.

Grantham, B. D., and V. A. Zammit. “Role of Carnitine Palmitoyltransferase I in the Regulation of Hepatic Ketogenesis during the Onset and Reversal of Chronic Diabetes.” Biochemical Journal 249, no. 2 (January 15, 1988): 409–14. https://doi.org/10.1042/bj2490409.

Greenberg, Cheryl R., Louise A. Dilling, G. Robert Thompson, Lorne E. Seargeant, James C. Haworth, Susan Phillips, Alicia Chan, et al. “The Paradox of the Carnitine Palmitoyltransferase Type Ia P479L Variant in Canadian Aboriginal Populations.” Molecular Genetics and Metabolism 96, no. 4 (April 2009): 201–7. https://doi.org/10.1016/j.ymgme.2008.12.018.

Akkaoui, Marie, Isabelle Cohen, Catherine Esnous, Véronique Lenoir, Martin Sournac, Jean Girard, and Carina Prip-Buus. “Modulation of the Hepatic Malonyl-CoA–carnitine Palmitoyltransferase 1A Partnership Creates a Metabolic Switch Allowing Oxidation of de Novo Fatty Acids1.” Biochemical Journal 420, no. 3 (June 15, 2009): 429–38. https://doi.org/10.1042/BJ20081932.

Effects of Polyunsaturated Fat on Ketogenesis and its Relevance to the Arctic Variant

Fuehrlein, Brian S., Michael S. Rutenberg, Jared N. Silver, Matthew W. Warren, Douglas W. Theriaque, Glen E. Duncan, Peter W. Stacpoole, and Mark L. Brantly. “Differential Metabolic Effects of Saturated versus Polyunsaturated Fats in Ketogenic Diets.” The Journal of Clinical Endocrinology and Metabolism 89, no. 4 (April 2004): 1641–45. https://doi.org/10.1210/jc.2003-031796.

Lemas, Dominick J., Howard W. Wiener, Diane M. O’Brien, Scarlett Hopkins, Kimber L. Stanhope, Peter J. Havel, David B. Allison, Jose R. Fernandez, Hemant K. Tiwari, and Bert B. Boyer. “Genetic Polymorphisms in Carnitine Palmitoyltransferase 1A Gene Are Associated with Variation in Body Composition and Fasting Lipid Traits in Yup’ik Eskimos.” Journal of Lipid Research 53, no. 1 (January 1, 2012): 175–84. https://doi.org/10.1194/jlr.P018952.

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