Ketogenic Ratio Determines Metabolic Effects of Macronutrients and Prevents Interpretive Bias

Abstract

Thomas Seyfried remarked in his book [(1), page 6]: “The definition of ketogenic diet allows for considerable leeway in food choices as long as the individual has reduced blood glucose and is producing ketones.” Unfortunately, these parameters are lacking in many if not most of studies into metabolic effects of macronutrients. Meanwhile, there is a precise way to predict whether or not a diet will induce ketosis and the aim of this opinion article is to advocate a broader usage of this way. Why is this so important? Excess of carbohydrate intake typical for consumers of the Western diet may cause detrimental effects on metabolism and increase risks of the onset and progression of many neurodegenerative diseases (2–4). On the other hand, diets high in fat and low in carbohydrates decrease appetite, probabilities of food addiction and obesity, and are neuroprotective (5, 6). Carbohydrate restriction induces physiological changes which are very similar to the well documented beneficial effects of calorie restriction (7, 8). Conversely, the hallmark of high-carbohydrate diets is homeostatic inadequacy (9), an overproduction of reactive oxygen species and advanced glycation products, both of which are implicated in neuroinflammation and neurodegeneration (10–12). However, the meaning of “high” or “low” in diets' definition has been drifting away from the previously established quantitative criterion known as ketogenic ratio. Almost a century ago, Woodyatt (13) wrote: “antiketogenesis is an effect due to certain products which occur in the oxidation of glucose, an interaction between these products on the one hand and one or more of the acetone bodies on the other.” The ketogenic ratio (KR), as proposed by Shaffer (14), is a ratio of the sum of ketogenic factors to the sum of antiketogenic factors: KR = K/AK. The antiketogenic part of the equation invariably equals 1 so the KRs are always expressed as 2:1, 4:1, etc. For the sake of economy of reading, we leaved out the repeating part not bearing any information and mention only the informative digit. Shaffer concluded that the maximal ratio compatible with the oxidation of the “ketogenic” molecules becomes possible at the KR = 1, making KRs below 1 antiketogenic and KRs above 2 ketogenic. Wilder and Winter (15) described the KR of a food in terms of times the fat content exceeds the amount of carbohydrate and protein combined, roughly. The reasoning was based on their own experimental observation that fats are predominantly ketogenic (90%), carbohydrates are almost 100% anti-ketogenic, and protein is both ketogenic and antiketogenic, 46–58% respectively. They arrived, along with Woodyatt and Sansum (13), at the conclusion that KR for induction of ketogenesis should be 2 or higher while the upper limit of antiketogenesis is 1. In 1980, Withrow (16) modified the equation and since that time, the equation looked like this: KR = (0.9 F + 0.46 P): (C + 0.58 P + 0.1 F) where F is grams of fat; P is grams of protein and C is grams of carbohydrate. Currently, this equation is rarely used in nutrition research and less so in dietetic practice, which is regrettable since properly calculated KRs reveals interesting patterns of diet effects. Previously (9), using the Withrow's equation, we calculated KRs in a number of diets and came to conclusion that the watershed in the group of effects occurs at KR of about 1.7. Above this value, metabolic features of diets were characteristic for ketogenesis, while below this value, they were characteristic for the obesogenic high-fat diet (oHFD), which, in contrast to the diet resulting in ketosis (KD), is high in fat but also in carbohydrates. Here, we analyzed three groups of diets in order to compare our observation regarding the watershed with the classification of diets made by the authors of 62 studies, in which it was possible to calculate KRs. We can see that there is no common criteria in choosing diet compositions for the “normal control” group to start with (Figure 1A). The vast majority of “normal control” diets are clearly anti-ketogenic (KRs below or equal 1). The oHFD group of diets had broader spectrum of KRs ranging from the anti-ketogenic 0.456 to clearly ketogenic 2.994. The KRs of diets, which were considered ketogenic by the authors, ranged especially broadly: from 0.36 to above 6. The macronutrient compositions of oHFD diets and KDs overlap although the obesogenic oHFD is discussed in literature as diametrically different from the KD. The metabo- and neuroprotective effects of KD are experimentally and clinically confirmed, however, the low compliance rate of the strict KD caused mass attempts to reduce the KR below KR = 2, which for a century used to be the minimal accepted value to consider a diet ketogenic. Figure 1. (A) Green line, theoretical threshold of ketogenesis; dashed green line, empirical threshold of ketogenesis. Red line, theoretical threshold of anti-ketogenesis; dashed red line KR = 0.5. Vertical axis, ketogenic ratios. Horizontal axix, original studies, first author and year (17–50). (B) Ketogenic ratios of diets below the ketogenic threshold. Calculated basing on data extracting from the studies (25, 51–54). Gray curves in (B,C) trendlines. (C) Body-mass loss on diets below the ketogenic threshold. VLCD, very low carbohydrate diet; MAD, modified Atkins diet; Zone, the Zone diet; KLC, ketogenic low carbohydrate diet; WW, Weight Watchers diet; VLFD, very low fat diet; NLC, non-ketogenic low carbohydrate diet. An example is the Modified Atkins Diet (MAD) first tried at The Johns Hopkins Hospital. It is a protocol replicating the induction phase of the original Atkins diet. MAD is composed of approximately 10% energy from carbohydrates, 30% from protein, and 60% from fat, no calorie restriction...