Effect of a Sodium and Calcium DL-β-Hydroxybutyrate Salt in Healthy Adults

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Background

Ketone body therapy and supplementation are of high interest for several medical and nutritional fields. The intake of ketone bodies is often discussed in relation to rare metabolic diseases, such as multiple acyl-CoA dehydrogenase deficiency (MADD), that have no alternatives for treatment.

Case reports showed positive results of therapy using ketone bodies. The number of ketone body salts offered on the wellness market is increasing steadily. More information on the kinetics of intake, safety, and tolerance of these products is needed.

Methods

In a one-dose kinetic study, six healthy subjects received an intervention (0.5 g/kg bw) using a commercially available ketone body supplement. The supplement contained a mixture of sodium and calcium D-/L-β-hydroxybutyrate (βHB) as well as food additives. The blood samples drawn in the study were tested for concentrations of D-βHB, glucose, and electrolytes, and blood gas analyses were done. Data on sensory evaluation and observed side effects of the supplement were collected. The product also went through chemical food analysis.

Results

The supplement led to a significant increase of D-βHB concentration in blood 2.5 and 3 h after oral intake (p = 0.033; p =0.043). The first significant effect was measured after 2 h with a mean value of 0.598 ± 0.300 mmol/L at the peak, which was recorded at 2.5 h. Changes in serum electrolytes and BGA were largely unremarkable. Taking the supplement was not without side effects. One subject dropped out due to gastrointestinal symptoms and two others reported similar but milder problems. Conclusions. Intake of a combination of calcium and sodium D-/L-βHB salt shows a slow resorption with a moderate increase of D-βHB in serum levels. An influence of βHB salts on acid-base balance could not be excluded by this one-dose study. Excessive regular consumption without medical observation is not free of adverse effects. -e tested product can therefore not be recommended unconditionally.

1. Introduction Interest in the importance of ketone bodies has risen in the recent past. Ketone bodies are an alternative fuel produced in the liver, in a process referred to as ketogenesis, in the event of reduced availability of glucose [1]. Insulin inhibits ketogenesis as opposed to glucagon and epinephrine, which both stimulate this process [2–4]. The base material is acetylCoA which is derived from the β-oxidation of fatty acids. -e basis of all three “ketone” bodies is acetoacetate. Acetoacetate can then either be reduced to beta-hydroxybutyrate (βHB), or acetone is generated by spontaneous decarboxylation of acetoacetate. Only acetoacetate and βHB are relevant for energy expenditure [5, 6]. -e maximum amount of daily ketone body production in adults is 150 g [7]. Normal postprandial βHB serum levels are less than 0.1 mmol/L [8]. -ey increase to approximately 0.1- 0.2 mmol/L after fasting overnight in healthy subjects [9]. The term ketosis describes an increased concentration of ketone bodies in blood. In clinical application, ketosis is often defined as a concentration of ketone bodies in the range of 2– 7 mmol/L and 3–5 mmol/L in therapy [10, 11].

The human organism has two nutrition-related ways of reaching ketosis. The first is starvation and the second is a high fat and at the same time low carbohydrate (HFLC) diet which is also known as a ketogenic diet [8, 12]. Ketosis can also be reached by an energy deficit caused by prolonged exercise [13]. In all cases, the organism reacts by an increasing ketone body production because of the decreased availability of glucose and therefore making the alternative fuel, ketone bodies, necessary as brain fuel or as energy substrate for other tissues, especially muscle [1, 8]. The main difference between the two nutrition-related states of ketosis is that in starvation fat reserves are used for ketone body synthesis and in HFLC fat from daily nutrition [8, 12].

Aside from the nutritional trend of low-carb diets with a maximal βHB serum concentration of 0.4 mmol/L, ketone bodies and specific diet forms like the ketogenic diet are of high scientific interest [14, 15].

There are different types of clinically relevant ketogenic diets. The milder forms are the low glycaemic index diet (LGID) and the modified Atkins diet (MAD) where carbohydrate intake is limited to 15 grams per day. More stringent are the medium chain triglycerides (MCT) diet as well as the 3 :1 and the 4 :1 classical ketogenic diets. The ratio depicts the fat contents in relation to the sum of carbohydrates and proteins based on their weight [16]. A well-known problem of ketogenic diets is limited patient compliance [17]. The daily intake of high amounts of fat is not tasty and has negative effects on the quality of life. Carbohydrate restriction is often even more difficult to adhere to. Adverse effects, especially soon after starting the diet, are often recorded and lead to dropouts. Typical undesirable side effects of the traditional ketogenic diet are gastrointestinal discomfort, weight loss, and negative changes in lipid profiles [18]. The application of moderate (≤50 g carbohydrates per day) ketogenic diets for weight loss show partially different effects when compared to clinically applied ketogenic diets. Positive effects on blood lipids, blood pressure, and weight are reported in obese subjects [19]. There are various very low carbohydrate and ketogenic trend diets that are milder than medical diets because trend diets have a lower fat content. The palatability of food in medical or trend diets increases strongly with the introduction of more carbohydrates and protein to the daily nutrition [20, 21].

The ketogenic diet has proven to be an effective therapy for epilepsy, although not only the anticonvulsive effect is used in medicine. In addition, some inherited metabolic diseases of glucose uptake or metabolism, for example, the GLUT1 or pyruvate dehydrogenase deficiency, are treated using ketogenic diets to ensure sufficient energy supply [22].

In special severe metabolic diseases of β-oxidation, like multiple acyl-CoA dehydrogenase deficiency (MADD), a direct intake of ketone bodies for energy supply is necessary. Inducing ketogenesis using normal food products is not possible due to the impairment of fatty acid oxidation. -e genetic defect in the electron transport flavoprotein or the electron transport flavoprotein oxyreductase causes a dysfunction of all acyl-CoA dehydrogenases in β-oxidation by the impaired oxidation of FADH2 to FAD [23]. For this disease, direct ketone body therapy using D,L-3-hydroxybutyrate sodium salt can be life-saving. Ketone body therapy in MADD is documented in some case reports. In treated patients, an increase of D-βHB in serum was detectable within one hour of intake and led to dramatic clinical improvements. After 2 and 9 months, MRI investigations showed a progressive decrease of leukodystrophy, a typical problem in MADD patients [24]. In cases of hypoglycemia caused by hyperinsulinisim, treatment with βHB as a supplement has been used without any adverse side effects and increased the serum concentration of D-βHB [25].

Good efficacy of ketogenic diets is clouded by poor practicability and the necessity of maintaining a constant ketosis during the day. -erapeutic levels can be achieved more easily through oral intake of βHB [10]. The direct oral intake of ketone body salts or acid, as described in some case reports, may not be totally free of health risks. Possible adverse side effects are cation overload or acidosis/alkalosis [26]. Newer publications on ketone body salts concentrate on their application in sports [27, 28]. However, available knowledge is still very limited. To manage potential problems, researchers are concentrating on synthesizing ketone body esters consisting of the primary ketone βHB and an alcohol, for example 1,3-butanediol [29].

Supplements containing ketone bodies have potential applications in cases of severe metabolic diseases, cancer, neurodegenerative disease, and many more. Apart from the medical use, such supplements are also of interest for lifestyle applications such as weight loss [30].

In an Internet search of the worldwide supplement market, a lot of products with βHB as the main ingredient are available since 2015. The first available product was a simple mixture of calcium and sodium βHB salt with an added flavor. There is currently no scientific opinion or direct testing published about products with a calcium and sodium βHB salt as the main ingredient. The aim of this study is to provide additional scientific information for an easily available ketone body salt mixture and discuss the potential benefit of such products in clinical application.

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