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If the PG continues to fall, the counter-regulatory hormones glucagon, cortisol, growth hormone, epinephrine (adrenaline) and norepinephrine (noradrenaline) are released into circulation, and the breakdown of triglycerides to glycerol and fatty acids in the adipocytes (lipolysis) occurs, Fig. 1 [10,11,12]. The glycerol is then converted to glucose in the liver (gluconeogenesis). Both glycerol and amino acids serve as substrates for glucose production in the hormonally controlled gluconeogenesis. The free fatty acids from lipolysis are processed by liver cell mitochondria into acetoacetate (AcAc), beta-hydroxybutyrate (BOHB), and, to a lesser degree, acetone, which together are named ketone bodies. These ketone bodies are an alternative source of energy for the brain and muscles when glucose is unavailable [13, 14].
SLC16A1 codes for monocarboxylase transporter 1 (MCT1), which mediates transport of pyruvate, lactate and ketone bodies across cell membranes. Patients with heterozygous or homozygous inhibiting mutations in SLC16A1 presented with moderate or profound ketosis and sometimes hypoglycemia at fasting or during infections, with onset in the first years of life [40, 47, 48]. In some of the patients, migraine, exercise intolerance, developmental delay, microcephaly and abnormal MRI of the brain were noted.
Nausea and vomiting caused by ketones may lead to further decline in PG if hyperketosis is not recognized and treated. The acute treatment principle includes administration of high glycemic index (i.e. dextrose-rich) foods or drinks to provide energy from glucose metabolism instead of fatty acid metabolism which leads to further ketone body formation.
Just before and after the HD session, in addition to standard parameters, ketone bodies (AcAc, β-HB) were measured in arterial serum samples obtained from the arteriovenous fistula using commercially available kits. Arterial blood samples obtained simultaneously were measured for acid-base parameters (pH, bicarbonate) using a blood gas analyzer. Arterial ketone body (AcAc/β-HB) ratio was estimated as redox state in liver mitochondria capable of producing ATP . AcAc and β-HB were measured using commercially available calorimetric assay kits obtained from Funakoshi (Tokyo, Japan) and BioAssay Systems (Hayward, CA), respectively. Glycoalbumin (GA), a clinically relevant parameter for glycemic control in HD patients that is not influenced by either the presence of anemia or usage of an erythropoiesis-stimulating agent , in contrast to HbA1c, was measured as previously described .
Participants in both groups were given a daily multivitamin mineral supplement. Each group was counseled in exercise and diet during a single group session. Participants in the Lc+Ex group were given information on the rationale and implementation of the dietary intervention and were given a commercially available book on a low carbohydrate ketogenic diet (Slank med ketolysekuren: en enklere vei til et lettere liv; "Slim with ketolysis: A simpler way to a lighter life")  in addition to handouts. The preparation of food was self administered. No restrictions were made regarding energy content, fat and protein content or fatty acid composition. The only restriction was on intake of carbohydrates, and the goal was to restrict carbohydrate intake until ketone bodies were detectable in the urine. The presence of ketone bodies was detected with a semi quantitative method using urine reagent strips (Ketolyse AS). The reagent strips indicated the concentration of acetone and acetoacetic acid in the urine. Participants were told to start the intervention with less than 20 g carbohydrate per day and to gradually increase the ingestion of carbohydrates at their convenience, as long as they maintained a color change on the urine reagent strips. The diet intervention was thus defined as a carbohydrate restriction that caused positive tests for urinary ketone bodies. Participants were told that they could consume unlimited amounts of meats, fish, eggs, cheeses, margarines, butters and oils. They were further instructed to add low carbohydrate food to their diet as they saw fit.
Note that high serum glucose levels may lead to dilutional hyponatremia; high triglyceride levels may lead to factitious low glucose levels; and high levels of ketone bodies may lead to factitious elevation of creatinine levels.
Hepatic gluconeogenesis, glycogenolysis secondary to insulin deficiency, and counter-regulatory hormone excess result in severe hyperglycemia, while lipolysis increases serum free fatty acids. Hepatic metabolism of free fatty acids as an alternative energy source (ie, ketogenesis) results in accumulation of acidic intermediate and end metabolites (ie, ketones, ketoacids). Ketone bodies have generally included acetone, beta-hydroxybutyrate, and acetoacetate. It should be noted, however, that only acetone is a true ketone, while acetoacetic acid is true ketoacid and beta-hydroxybutyrate is a hydroxy acid.
The absence of insulin, the primary anabolic hormone, means that tissues such as muscle, fat, and liver do not uptake glucose. Counterregulatory hormones, such as glucagon, growth hormone, and catecholamines, enhance triglyceride breakdown into free fatty acids and gluconeogenesis, which is the main cause for the elevation in serum glucose level in DKA. Beta-oxidation of these free fatty acids leads to increased formation of ketone bodies.
Secondary consequences of the primary metabolic derangements in DKA include an ensuing metabolic acidosis as the ketone bodies produced by beta-oxidation of free fatty acids deplete extracellular and cellular acid buffers. The hyperglycemia-induced osmotic diuresis depletes sodium, potassium, phosphates, and water.
Excessive oxidative stress can be generated byforcing cancer cells to produce energy via mitochondrial oxidation,which is expected to cause anticancer effects without injury tobenign cells, as for the latter it is a normal metabolic process(4). A previous study indicated thatketone bodies and medium-chain fatty acids (MCFAs) may be used as atool to induce cancer cells to switch between glycolysis andoxidative phosphorylation for energy production, indicating thatketogenic and MCFA-enriched diets may be beneficial in cancertherapy (5).
In mitochondria, fatty acids are metabolized toacetyl-CoA via β-oxidation, which can be diverted to the formationof ketone bodies under the conditions of glucose starvation(5,6).β-hydroxybutyric acid (β-HBA, also termed 3-HBA) is one of thethree ketone bodies generated from fatty acids; it has beenrevealed that 3-HBA can be used for energy production inmitochondria through the tricarboxylic acid cycle, where it isconverted into acetoacetic acid and then to acetyl-CoA (7,8). Ketogenicdiets rich in medium-chain triglycerides demonstrated inhibitoryeffects on cancer growth, and it was observed that prostate cancercells had lower ability to utilize dietary fatty acids comparedwith normal prostate cells, indicating possible therapeuticpotential. Lauric acid (LAA) is an MCFA with an aliphatic tail of12 carbons, which, contrary to long-chain fatty acids (LCFAs), canbe transported to the mitochondrial intermembrane space directlywithout the carnitine shuttle (9).Therefore, LAA is utilized through β-oxidation with higher efficacythan LCFAs (10). The present studyexamined the effect of 3-HBA and LAA on cancer cell proliferation,oxidative stress and stemness, with the aim of providingmechanistic insights into a potentially therapeutic effect ofketogenic diets for patients with cancer.
Cancer cells can utilize ketone bodies or LAA(16,18). It was previously revealed that gastriccancer cells could continue growing in glucose-free mediumsupplemented with ketone bodies (16). Utilization of ketone bodies in gastriccancer cells is regulated by the expression of SCOT, a key enzymeinvolved in ketone body metabolism (16), and it was reported that neuroblastomacells were unable to use ketone bodies as an energy source, due todecreased SCOT expression (18).
Therefore, the present study examined the expressionof MCT1, MCT5 and SCOT, which enable the utilization of 3-HBA andLAA in colon cancer cells. However, the levels of SCOT expressionwere low, which is consistent with the lower SCOT levels in cancercells compared with in cancer-associated fibroblasts observed incolorectal cancer (19). By contrast,the carnitine shuttle enzyme carnitine palmitoyltransferase 1A(CPT1), which is important for fatty acid transport intomitochondria, was expressed at high levels in CT26 cells (20). The experimental concentration of 3-HBA(1 mM) in the present study was equivalent to serum levels ofketone bodies present in individuals fed a carbohydrate-limiteddiet (21). The experimentalconcentration of LAA was also equivalent to the serum fatty acidconcentration (22). Thus, LAA mayprovide higher mitochondria-activating effect on energy metabolismcompared with 3-HBA.
In normal tissues, SCFAs and MCFAs inhibitglycolysis and stimulate lipogenesis or gluconeogenesis (15). SCFAs and MCFAs exhibit no or weakprotonophoric and lytic activities in mitochondria, and decreasethe efficacy of oxidative ATP synthesis (15). However, SCFAs and MCFAs also increasethe mitochondrial respiratory capacity in normal physiological andinflammatory conditions (23). MCFAsalso stimulate fatty acid oxidization and energy production inmitochondria in type II skeletal muscle (24). In cancer, SCOT, the rate-limitingenzyme for the production of ketone bodies, and CPT1, the carnitineshuttle protein, is associated with the cell metastatic potential,as evidenced by their increased expression in the highly metastaticSW620 cells, as compared with in the low metastatic parental SW480cells (25). In the present study,3-HBA and LAA decreased lactate fermentation, particularly underglucose starvation, indicating that 3-HBA and LAA switch the energyproduction pathway from glycolysis and lactate fermentation tooxidative phosphorylation. 2b1af7f3a8