Ketogenic Diets for Cancer-1. “What makes you think that ketone bodies will help?”
Posted on 9/2/20
By Drs. Eugene J. Fine and Richard D. Feinman
That’s the question we always get. Or something like that. What follows is our answer as laid out at in a campaign we ran on experiment.com in 2016. We were very lucky in that many people responded to the campaign, and we are most grateful for the many contributions. The campaign intended to follow up on Dr. Fine’s pilot study of ten advanced cancer patients on ketogenic diets and in vitro and animal models that we are carrying out in parallel.
The evidence supporting carbohydrate restriction, or specifically, ketogenic diets, in cancer remains largely indirect and speculative. The direct patient studies have been small in number and, if sometimes compelling, are not easily generalizable. The major lines of research that encourage us to pursue ketogenic diets reside in the importance of the hormone insulin as a major control point. While cancer constitutes a breakdown in control and organization, at the same time, it expresses itself as a major builder, making cell material without bound. Insulin as an anabolic (building-up) hormone will be a big player. Much of life really rests with controlling vital reactions as much as expressing them. So it has been observed for some time that patients with diabetes have higher risk of cancer. Epidemiological and other kinds of studies are generally consistent with the idea although different cancers are more or less closely associated with diabetes (Figure below) . Drugs employed as diabetes therapy, particularly metformin, have been found to have beneficial effects in cancer as well. Metformin reduces the risk of developing cancer although the effects on mortality are not clear cut. We made the case, in our critical review, that dietary carbohydrate restriction is the first line of treatment for type 2 diabetes and the best adjunct for pharmacology in type 1 diabetes. Recent publications from Virta Health (references below) have nailed it.
The association between cancer and diabetes in combination with the benefits of carbohydrate restriction in diabetes constitute one big connection. In dietary approaches, however, it is total caloric reduction that has received the most attention and, in fact, experiments show that if implemented as stated, calorie restriction represents a reliable approach to prevention and treatment of cancer, particularly in animal models. It is unknown how much of the effect is due to de facto reduction in particular macronutrients but when tested, carbohydrate reduction as the means of reducing calories proves most effective. An important study by Tannenbaum in 1945 (!) found that a carcinogen-induced sarcoma in mice was repressed by reduction in total calories, but if calories were reduced by specifically lowering the carbohydrate intake, there was an enhanced response.
Impressive cancer prevention with calorie restriction in animal models has been repeated many times. Oddly, the protocol is most often presented as caloric restriction. Odd, in that this appears in sophisticated scientific papers where the downstream effects of the stimulation may pinpoint twenty molecular components and where the molecular targets of the “nutrients” are characterized and may specifically be the insulin receptor and the related IGF-1 (insulin-like growth factor-1) receptor. (Insulin is probably most important in that it stimulates IGF-1 activity by reducing the levels of the associated binding proteins). In these studies, where total caloric reduction is the independent variable, the involvement of insulin and the insulin-dependent downstream pathways have been shown to be involved.
Probably most salient in the mind of researchers on ketogenic diets for cancer is the Warburg effect. It is now appreciated that the apparent reliance of tumors on glucose for fuel and the apparent reliance on glycolysis at the expense of aerobic metabolism, is a key observation that has been insufficiently explored. The effect provides motivation and clues for exploring the metabolic approach to cancer. Ketogenesis is intimately involved with and controlled by insulin. Warburg thought that all cancers showed this glycolytic phenotype. While that is not true, a large number do. Of significance is that one tumor that does not show this behavior, prostate cancer, is the outlier in the figure above on relation to diabetes to cancer risk. The next post will start from some basic biochemistry and explain why (and how) we think that the Warburg effect points to the potential value of ketogenic diets.
References.
1. Hyde, P., Sapper, T., Crabtree, C. et al. Dietary carbohydrate restriction improves metabolic syndrome independent of weight loss JCI Insight. 2019; 4:(12)e128308.
2. Hallberg, S.J., McKenzie, A.L., Williams, P.T. et al. Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non Randomized, Controlled Study. Diabetes Ther 9, 583–612 (2018) doi:10.1007/ s13300-018-0373-9 2.
3. Athinarayanan SJ, Adams RN, Hallberg SJ, et al. (2019) Long-Term Effects of a Novel Continuous Remote Care Intervention Including Nutritional Ketosis for the Management of Type 2 Diabetes: A 2-Year Non-randomized Clinical Trial. Front. Endocrinol. 10:348.
4. Hallberg SJ, Dockter NE, Kushner JA, Athinarayanan SJ. Improving the scientific rigour of nutritional recommendations for adults with type 2 diabetes: A comprehensive review of the American Diabetes Association guideline-recommended eating patterns. Diabetes Obes Metab. 2019;21:1769–1779.