High Concentrations Of Ketone Bodies Research Articles

FEATURES OF MANIFESTATION OF NONALCOHOLIC STEATOHEPATITIS IN OBESE PATIENTS AFTER LAPAROSCOPIC SLEEVE GASTRECTOMY

The state of energy starvation is the main phenomenon of the early postoperative period of bariatric surgery. All organs and systems of the body undergo such changes. Under normal physiological conditions, with the development of energy hunger, there is an excitation of metabolic centres in the hypothalamic-pituitary system of the brain. Transmitted impulses from chemoreceptor cells increase lipolysis, which ultimately leads to the mobilisation of large amounts of fatty acids from the fat depot to the liver. Excessively high concentrations of ketone bodies due to rapid weight loss are accompanied by the development of ketonemia, the severity of which depends not only on the compensatory capabilities of the body but also on the condition of the liver. Ketonemia is one of the common side effects reported by patients after bariatric surgery. Despite this, the evidence for the incidence of ketonemia after various bariatric surgeries and the mechanism of the development of this phenomenon is very limited. In this regard, this scientific article is devoted to the features of the manifestation of ketonemic syndrome in obese patients after the most popular type of bariatric surgery - laparoscopic longitudinal resection of the stomach.

Genome-wide association study and functional analyses for clinical and subclinical ketosis in Holstein cattle

Ketosis is one of the most frequent metabolic diseases in high-yielding dairy cows and is characterized by high concentrations of ketone bodies in blood, urine, and milk, causing high economic losses. The search for polymorphic genes, whose alleles have different effects on resistance to developing the disease, is of extreme importance to help select less susceptible animals. The aims of this study were to identify genomic regions associated with clinical and subclinical ketosis (β-hydroxybutyrate concentration) in North American Holstein dairy cattle and to investigate these regions to identify candidate genes and metabolic pathways associated with these traits. To achieve this, a GWAS was performed for 4 traits: clinical ketosis lactation 1, clinical ketosis lactation 2 to 5, subclinical ketosis lactation 1, and subclinical ketosis lactation 2 to 5. The estimated breeding values from 77,277 cows and 7,704 bulls were deregressed and used as pseudophenotypes in the GWAS. The top-20 genomic regions explaining the largest proportion of the genetic variance were investigated for putative genes associated with the traits through functional analyses. Regions of interest were identified on chromosomes 2, 5, and 6 for clinical ketosis lactation 1; 3, 6, and 7 for clinical ketosis lactation 2 to 5; 1, 2, and 12 for subclinical ketosis lactation 1; and 20, 11, and 25 for subclinical ketosis lactation 2 to 5. The highlighted genes potentially related to clinical and subclinical ketosis included ACAT2 and IGF1. Enrichment analysis of the list of candidate genes for clinical and subclinical ketosis showed molecular functions and biological processes involved in fatty acid metabolism, lipid metabolism, and inflammatory response in dairy cattle. Several genomic regions and SNPs related to susceptibility to ketosis in dairy cattle that were previously described in other studies were confirmed. The novel genomic regions identified in this study aid to characterize the most important genes and pathways that explain the susceptibility to clinical and subclinical ketosis in dairy cattle.

Effects of ketogenic diet and ketone bodies on the cardiovascular system: Concentration matters.

Ketone bodies have emerged as central mediators of metabolic health, and multiple beneficial effects of a ketogenic diet, impacting metabolism, neuronal pathologies and, to a certain extent, tumorigenesis, have been reported both in animal models and clinical research. Ketone bodies, endogenously produced by the liver, act pleiotropically as metabolic intermediates, signaling molecules, and epigenetic modifiers. The endothelium and the vascular system are central regulators of the organism’s metabolic state and become dysfunctional in cardiovascular disease, atherosclerosis, and diabetic micro- and macrovascular complications. As physiological circulating ketone bodies can attain millimolar concentrations, the endothelium is the first-line cell lineage exposed to them. While in diabetic ketoacidosis high ketone body concentrations are detrimental to the vasculature, recent research revealed that ketone bodies in the low millimolar range may exert beneficial effects on endothelial cell (EC) functioning by modulating the EC inflammatory status, senescence, and metabolism. Here, we review the long-held evidence of detrimental cardiovascular effects of ketoacidosis as well as the more recent evidence for a positive impact of ketone bodies—at lower concentrations—on the ECs metabolism and vascular physiology and the subjacent cellular and molecular mechanisms. We also explore arising controversies in the field and discuss the importance of ketone body concentrations in relation to their effects. At low concentration, endogenously produced ketone bodies upon uptake of a ketogenic diet or supplemented ketone bodies (or their precursors) may prove beneficial to ameliorate endothelial function and, consequently, pathologies in which endothelial damage occurs.

Ketosis an Old Story Under a New Approach

Ketosis, characterized by high concentrations of ketone bodies in the blood, urine, and milk, affects a considerable number of cows immediately after calving. Although much is known about ketosis, dairy cows continue to be affected in every herd world-wide. Cows affected by ketosis are treated with palliative treatments after the disease is diagnosed. This is a very expensive approach and costs the dairy industry extra expenses, contributing to lower profitability of dairy herds. In this review article, we summarize the mainstream view on ketosis, classification of ketosis into three types, current diagnostic approaches to ketosis, and the economic impact of ketosis on dairy farms. Additionally, we discuss the most recent applications of the new ‘omics’ science of metabolomics in studying the etiopathology of ketosis as well as its contribution in identification of novel screening or diagnostic biomarkers of ketosis.

High levels of fatty acids inhibit β-casein synthesis through suppression of the JAK2/STAT5 and mTOR signaling pathways in mammary epithelial cells of cows with clinical ketosis.

Ketosis is a metabolic disease of dairy cows often characterized by high concentrations of ketone bodies and fatty acids, but low milk protein and milk production. The Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) and the mechanistic target of rapamycin (mTOR) signaling pathways are central for the regulation of milk protein synthesis. The effect of high levels of fatty acids on these pathways and β-casein synthesis are unknown in dairy cows with clinical ketosis. Mammary gland tissue and blood samples were collected from healthy (n = 15) and clinically-ketotic (n = 15) cows. In addition, bovine mammary epithelial cells (BMEC) were treated with fatty acids, methionine (Met) or prolactin (PRL), respectively. In vivo, the serum concentration of fatty acids was greater (P > 0.05) and the percentage of milk protein (P > 0.05) was lower in cows with clinical ketosis. The JAK2-STAT5 and mTOR signaling pathways were inhibited and the abundance of β-casein was lower in mammary tissue of cows with clinical ketosis (P > 0.05). In vitro, high levels of fatty acids inhibited the JAK2-STAT5 and mTOR signaling pathways (P > 0.05) and further decreased the β-casein synthesis (P > 0.05) in BMEC. Methionine or PRL treatment, as positive regulators, activated the JAK2-STAT5 and mTOR signaling pathways to increase the β-casein synthesis. Importantly, the high concentration of fatty acids attenuated the positive effect of Met or PRL on mTOR, JAK2-STAT5 pathways and the abundance of β-casein (P > 0.05). Overall, these data indicate that the high concentrations of fatty acids that reach the mammary cells during clinical ketosis inhibit mTOR and JAK2-STAT5 signaling pathways, and further suppress β-casein synthesis.

Risk Factors for Hyperketonemia in Cleft Lip and Palate Infants During General Anesthesia

The purpose of the present study was to investigate the risk factors for hyperketonemia with respect to patient age, the starting time of anesthesia (morning or afternoon), and the preoperative liquid intake when glucose was administered to infants before and during general anesthesia to avoid the hyperketonemia resulting from lipid catabolism. The subjects were 147 healthy infants, including 55 infants 2 to 6 months old (cleft lip group) and 92 who were 10 to 24 months old (cleft palate [CP] group). For preoperative liquid intake, the infants were allowed to drink formula or breast milk for ≤ 5 hours before entering the operating room and 6.7% glucose solution for ≤ 2 hours before entering the operating room. As an intraoperative infusion, 195 mg/kg/hour of glucose was constantly administered. The levels of blood ketone bodies and glucose were measured at anesthesia induction and 2 hours after induction. Blood ketone body (β-hydroxybutyrate) concentrations of ≥ 1.0 mmol/L were considered abnormally high. The ketone body concentrations were abnormally high in 34 infants and normal in 113 infants. Significant differences were present in relation to age (P = .001) and age group (CP group, P < .001), and starting time of anesthesia (afternoon cases, P = .003). However, no difference in preoperative liquid intake was seen between groups. Logistic regression analysis suggested age group (CP group) and starting time of anesthesia (afternoon cases) as factors associated with elevated blood ketone body concentrations. The risk factors for abnormally high ketone body concentrations were age group (CP group) and starting time of anesthesia (afternoon cases).

Hyperketonemia impairs glucose metabolism in pregnant and nonpregnant ewes.

The present study was undertaken to test the hypothesis that high ketone body concentrations suppress endogenous production of glucose and in pregnant sheep facilitate development of pregnancy toxemia. Rates of endogenous glucose production [mmol.min(-1)], and rate constants of glucose turnover [min(-1)] were measured in seven 12-h fasted sheep in the presence of normo- and hyperketonemia by use of D-2-[(3)H]-glucose. The measurements were carried out in the same sheep during the nonpregnant nonlactating state, during late pregnancy (10 +/- 7 d antepartum) and during lactation (19 +/- 6 d postpartum). Hyperketonemia (5 to 7 mmol.L(-1)), similar to that present in spontaneous ovine pregnancy toxemia, was induced by continuous intravenous 4-h infusions of DL-beta-hydroxybutyrate (DL-BHB). Glucose turnover [mmol.min(-1)] in the same 7 nonpregnant nonlactating, late pregnant, and lactating sheep was significantly greater during normoketonemia (0.80, 1.16, 1.76) than during hyperketonemia (0.66, 0.92, 1.16, respectively). The rate constants of glucose turnover were not altered by elevation of the BHB concentration. The results demonstrated that high BHB concentrations significantly suppressed endogenous glucose production but showed no effect on glucose utilization. The suppressive effect of hyperketonemia on hepatic glucose production resulted in a significant reduction of plasma glucose concentration and was qualitatively the same in all three reproductive states. The results indicate that hyperketonemia, which is regularly present in late twin pregnant hypoglycemic sheep contributes significantly to the reduction of available glucose. This effect of hyperketonemia may invoke sustained hypoglycemia and may render the ewe into a vicious cycle that probably makes the animal refractory to treatment in most cases.

High β-hydroxybutyrate concentration in liver and skeletal muscle of newly hatched chicks

Characteristic changes in ketone body concentrations in blood, liver, and skeletal muscle were investigated in detail in newly hatched chicks. The concentration of β-hydroxybutyrate in the blood was maximal at hatch (0 day), markedly decreased to 3 days, then maintained at low levels, up to 14 days of age. The concentration of acetoacetate in blood, on the other hand, did not change after hatching but remained lower than that of β-hydroxybutyrate at all ages. In liver and muscles, the concentration of β-hydroxybutyrate changed in a manner similar to that in the blood. The muscle to blood ratio of the β-hydroxybutyrate concentration on days −1 and 0 was significantly higher than those at 1 through 14 days post-hatch. These results show that newly hatched chicks have the same high ketone body concentrations in the skeletal muscle, blood and liver. It is, hence, suggested that uptake of β-hydroxybutyrate by muscles is substantial or that ketogenesis, if any, occurs in muscles immediately before and after hatching of chicks.

Hyperketonemia and the impairment of udder defense: a review.

The objective of this study was to review the possible relationships between hyperketonemia and the function of phagocytes with respect to the bovine udder defense mechanism. We hypothesize that an increased incidence of clinical mastitis in high-producing cows is caused by the impairment of the udder defense mechanism during hyperketonemia. First, we review the acute phase of udder defense mechanisms after intramammary infection. The physiological changes of cows in negative energy balance are subsequently discussed. Finally, possible relationships between udder defense and physiological changes during negative energy balance, especially hyperketonemia, are reviewed. The three stages of an acute phase of udder defense are: (1) immediately eliminating invading pathogens by phagocytes, (2) releasing inflammatory substances, especially chemoattractants, and (3) migration of polymorphonuclear leukocytes into the infected udder. Leukocytes from hyperketonemia subjects show a lower capacity of the phagocytic defense mechanism. In addition, the phagocytic and bactericidal capacities of neutrophils are reduced when these cells are acting in the presence of high concentrations of ketone bodies. Lower amounts of cytokine production after bacterial infection are observed in ketotic subjects. The chemotactic capacity of blood leukocytes is impaired in leukocytes obtained from ketotic cows. Lower numbers of blood leukocytes are observed in ketotic cows. In conclusion, the impairment of the udder defense mechanism in negative energy balance cows seems related to hyperketonemia.

An investigation of the abnormal metabolic status of synovial fluid from patients with rheumatoid arthritis by high field proton nuclear magnetic resonance spectroscopy.

The 1H Hahn spin-echo NMR profiles of rheumatoid synovial fluids have been investigated and compared with those of matched serum samples. In addition to markedly elevated lactate and diminished glucose concentrations, inflammatory synovial fluids contained (i) substantially lower levels of NMR-detectable chylomicron-and very-low-density-lipoprotein-associated triacylglycerols which appear to have a shortened mean chain-length, and (ii) high concentrations of ketone bodies (predominantly 3-D-hydroxybutyrate), relative to those of corresponding paired serum samples. These observations confirm the abnormal metabolic status of the inflamed rheumatoid joint and provide evidence for an increased utilisation of lipids for fuel therein.

Glucose utilization by the placenta of anesthetized rats: effect of insulin, glucose, and ketone bodies.

Placental glucose metabolism and its regulation have been investigated in vivo in the rat using the radioactive 2-deoxyglucose technique. In the basal state, placental glucose utilization rates were similar on days 19 and 21 of gestation: 139 +/- 5 and 155 +/- 22 nmol/min/g at maternal blood glucose concentrations of 4.3 +/- 0.1 and 4.2 +/- 0.1 mmol/1. During hyperglycemic clamps, maternal glycemia was raised to 5.5 mmol/liter, a value similar to that during a meal in the rat. In this condition, the rate of placental glucose utilization at 19 days of gestation was increased by 85%. This was due not only to hyperglycemia but also to glucose-induced hyperinsulinemia. Indeed during hyperinsulinemic euglycemic clamps, placental glucose utilization showed a dose-response relationship to insulin (400 and 5000 microU/ml). At 21 days of gestation, placental glucose utilization was not affected by hyperglycemia or by hyperinsulinemia suggesting that in term placenta, glucose metabolism is no longer regulated. When 19-day pregnant rats were fasted for 48 and 96 h, the resulting low blood glucose and plasma insulin concentrations and the high ketone body concentrations induced, respectively, a 40 and 47% reduction of placental glucose utilization. The decrease in placental glucose utilization probably was due to both maternal hypoglycemia and long term adaptation to hyperketonemia. Indeed, the acute hyperketonemia in fed rats did not alter glucose utilization rate in placenta at 19 days of gestation. These data suggest that glucose metabolism in the preterm rat placenta is modulated in vivo by the maternal metabolic environment, particularly by maternal blood glucose and insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Monoacetoacetin and protein metabolism during parenteral nutrition in burned rats.

The effect of intravenous infusion of monoacetoacetin (glycerol monoacetoacetate) as a non-protein energy source was evaluated in burned rats. During 3 days of parenteral nutrition, in which animals received 14 g of amino acids/kg body wt. per day exclusively (group I) or with the addition of isoenergetic amounts (523 kJ/kg per day) of dextrose (group II), a 1:1 mixture of dextrose and monoacetoacetin (group III) or monoacetoacetin (group IV), significant decreases in urinary nitrogen excretion and whole-body leucine oxidation were observed in the three groups given additional non-protein energy as compared with group I. Serum ketone bodies (acetoacetate and 3-hydroxybutyrate) were decreased in rats given dextrose, whereas glucose and insulin increased significantly. Monoacetoacetin-infused animals (group IV) had high concentrations of ketone bodies without changes in glucose and insulin, whereas animals infused with both monoacetoacetin and glucose (group III) showed intermediate values. On day 4 of nutritional support, whole-body L-leucine kinetics were measured by using a constant infusion of L-[1-14C]leucine. In comparison with group I, the addition of dextrose or monoacetoacetin produced a significant decrease in plasma leucine appearance and release from whole-body protein breakdown. Gastrocnemius-muscle protein-synthesis rates were also higher in the three groups receiving additional non-protein energy. These findings suggest that monoacetoacetin can effectively replace dextrose as an intravenous energy source in stressed rats. Both fuels are similar in decreasing weight loss, nitrogen excretion, leucine release from whole-body protein breakdown and oxidation, in spite of differences in energy substrate and insulin concentrations.

Carrier-mediated uptake of lactate in rat hepatocytes. Effects of pH and possible mechanisms for L-lactate transport.

The rate of uptake and the distribution ratio between intra- and extracellular compartments of L- and D-lactate were studied in hepatocyte preparations from fed rats. L- and D-lactate uptake apparently depended on both passive diffusion and carrier-mediated components. The apparent Km of the high-affinity carrier for L-lactate was in the range of 1.8 mM. The reciprocal competitive inhibitions between isomers of lactate suggest that L- and D-lactate might be transported by distinct carriers. Lactate transport was inhibited by various anions; pyruvate was the most potent anion, whereas only high concentrations of ketone bodies were effective. Acidic extracellular pH enhanced lactate uptake, this effect being more pronounced for L-lactate. At low pH, L-lactate was concentrated into hepatocytes, but its affinity for the carrier appeared unchanged, suggesting the existence of a process gaining energy from the pH gradient across the cell membrane. In the hypothesis of a lactate/H+ symport, the affinity for H+ was not dependent on lactate concentration and the apparent Km for H+ corresponded to a pH of 7.34. No trans-stimulation of lactate uptake after prior loading of the cells with pyruvate or lactate was observed. The present data suggest that, at physiological concentrations, lactate uptake by the liver might be largely carrier-mediated and the rate of transport across the liver cell membrane may be of a magnitude relatively comparable to the rate of metabolism.

Effect of elevated substrates on substrate oxidation in normal and diabetic aorta.

The influence of elevated substrates (glucose, beta-hydroxybutyrate and palmitate) on the gated. The oxidation of 14C-glucose to 14CO2 was depressed in diabetic aorta at a glucose concentration of 5.6 mM in the incubation medium. The glucose oxidation in normal and mM. The oxidation of 14C-beta-hydroxybutyrate (0.5 and 1.5 mM) to 14CO2 was impaired in diabetic aorta, while the oxidation of 14C-palmitate (0.5 and 1.0 mM) to 14CO2 was unaltered. The oxidation of both substrates was concentration dependent. The glucose oxidation in normal rat aorta was reduced by addition of 3.0 and 6.0 mM of beta-hydroxybutyrate to the incubation medium, while 1.5 mM palmitate had no effect on the glucose oxidation. After incubation of normal rat aorta in MEM with glucose (20.0 mM) for 46 h the subsequently determined glucose oxidation was not influenced in comparison to the aorta incubated in 5.6 mM glucose. Incubation with 6.0 mM beta-hydroxybutyrate or 1.5 mM palmitate did not affect the aortic glucose oxidation. In rats which were infused for 24 h with glucose or beta-hydroxybutyrate to obtain diabetic levels of these substrates, there was no change in the aortic glucose oxidation compared to saline-infused controls. The present results suggests that the lowered glucose oxidation in diabetic vascular tissue is not caused by hyperglycemia or high concentrations of ketone bodies or free fatty acids in the diabetic state.

Activities of enzymes of ketone-body utilization in brain and other tissues of suckling rats.

1. The activities of 3-hydroxybutyrate dehydrogenase and 3-oxo acid CoA-transferase in rat brain at birth were found to be about two-thirds of those of adult rat brain, expressed per g wet wt. The activities rose throughout the suckling period and at the time of weaning reached values about three times higher than those for adult brain. Later they gradually declined. 2. At birth the activity of acetoacetyl-CoA thiolase in rat brain was about 60% higher than in the adult. During the suckling period there was no significant change in activity. 3. In rat kidney the activities of the three enzymes at birth were less than one-third of those at maturity. They gradually rose and after 5 weeks approached the adult value. Similar results were obtained with rat heart. 4. The activity of glutamate dehydrogenase (a mitochondrial enzyme like 3-hydroxybutyrate dehydrogenase and 3-oxo acid CoA-transferase) also rose in brain and kidney during the suckling period, but at no stage did it exceed the adult value. 5. Throughout the suckling period the total ketone-body concentration in the blood was about six times higher than in adult fed rats, and the concentration of free fatty acids in the blood was three to four times higher. 6. It is concluded that the rate of ketone-body utilization in brains of suckling rats is determined by both the greater amounts of the key enzymes in the tissue and the high concentrations of ketone bodies in the blood. In addition, the low activities of the relevant enzymes in kidney and heart of suckling rats may make available more ketone bodies for the brain.