Ketone bodies have beneficial metabolic activities, and the induction of plasma ketone bodies is a health promotion strategy. Dietary supplementation of sodium butyrate (SB) is an effective approach in the induction of plasma ketone bodies. However, the cellular and molecular mechanisms are unknown. In this study, SB was found to enhance the catalytic activity of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting enzyme in ketogenesis, to promote ketone body production in hepatocytes. SB administrated by gavage or intraperitoneal injection significantly induced blood ß-hydroxybutyrate (BHB) in mice. BHB production was induced in the primary hepatocytes by SB. Protein succinylation was altered by SB in the liver tissues with down-regulation in 58 proteins and up-regulation in 26 proteins in the proteomics analysis. However, the alteration was mostly observed in mitochondrial proteins with 41% down- and 65% up-regulation, respectively. Succinylation status of HMGCS2 protein was altered by a reduction at two sites (K221 and K358) without a change in the protein level. The SB effect was significantly reduced by a SIRT5 inhibitor and in Sirt5-KO mice. The data suggests that SB activated HMGCS2 through SIRT5-mediated desuccinylation for ketone body production by the liver. The effect was not associated with an elevation in NAD⁺/NADH ratio according to our metabolomics analysis. The data provide a novel molecular mechanism for SB activity in the induction of ketone body production.
Mice ; Animals ; Butyric Acid/metabolism* ; Ketone Bodies/metabolism* ; Liver/metabolism* ; Hydroxybutyrates/metabolism* ; Down-Regulation ; Sirtuins/metabolism* ; Hydroxymethylglutaryl-CoA Synthase/metabolism*

Heart failure (HF) has become a major challenge in the treatment of global cardiovascular diseases. Great progress has been made in the drug treatment of HF, however, rehospitalization rate and mortality of patients with HF are still high. Hence, there is an urgent need to explore new treatment strategy and new underlying pathogenic mechanisms. In recent years, some researchers have suggested that regulation of ketone body metabolism may become a potentially promising therapeutic approach for HF. Some studies showed that the oxidative utilization of fatty acids and glucose was decreased in the failing heart, accompanied by the increase of ketone body oxidative metabolism. The enhancement of ketone body metabolism in HF is a compensatory change during HF. The failing heart preferentially uses ketone body oxidation to provide energy, which helps to improve the body's cardiac function. This review will discuss the potential significance of ketone body metabolism in the treatment of HF from three aspects: normal myocardial ketone body metabolism, the change of ketone body metabolism in HF, the effect of ketogenic therapy on HF and its treatment.
Humans ; Heart Failure/metabolism* ; Myocardium/metabolism* ; Ketone Bodies/metabolism* ; Cardiovascular Diseases ; Fatty Acids/metabolism* ; Energy Metabolism

OBJECTIVES: Reduced glucose utilization in the main parts of the brain involved in memory is a major cause of Alzheimer's disease, in which ketone bodies are used as the only and effective alternative energy source of glucose. This study examined the effects of a low-carbohydrate and high-fat (LCHF) diet supplemented with a ketogenic nutrition drink on cognitive function and physical activity in the elderly at high risk for dementia.METHODS: The participants of this study were 28 healthy elderly aged 60-91 years showing a high risk factor of dementia or whose Korean Mini-Mental State Examination (K-MMSE) score was less than 24 points. Over 3 weeks, the case group was given an LCHF diet with nutrition drinks consisting of a ketone/non-ketone ratio of 1.73:1, whereas the control group consumed well-balanced nutrition drinks while maintaining a normal diet. After 3 weeks, K-MMSE, body composition, urine ketone bodies, and physical ability were all evaluated.RESULTS: Urine ketone bodies of all case group subjects were positive, and K-MMSE score was significantly elevated in the case group only (p=0.021). Weight and BMI were elevated in the control group only (p<0.05). Grip strength was elevated in all subjects (p<0.01), and measurements of gait speed and one leg balance were improved only in the case group (p<0.05).CONCLUSIONS: We suggest that adherence to the LCHF diet supplemented with a ketogenic drink could possibly influence cognitive and physical function in the elderly with a high risk factor for dementia. Further, we confirmed the applicability of this dietary intervention in the elderly based on its lack of any side effects or changes in nutritional status.
Aged ; Alzheimer Disease ; Body Composition ; Brain ; Cognition ; Dementia ; Diet ; Diet, High-Fat ; Gait ; Glucose ; Hand Strength ; Humans ; Ketone Bodies ; Leg ; Memory ; Motor Activity ; Nutritional Status ; Risk Factors

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is a rare inborn error of ketone body utilization, characterized by episodic or permanent ketosis. SCOT deficiency is caused by mutations in the OXCT1 gene, which is mapped to 5p13 and consists of 17 exons. A 12-month-old girl presented with severe ketoacidosis and was treated with continuous renal replacement therapy. She had two previously unrecognized mild-form episodes of ketoacidosis followed by febrile illness. While high levels of ketone bodies were found in her blood and urine, other laboratory investigations, including serum glucose, were unremarkable. We identified novel compound heterozygous mutations in OXCT1:c.1118T>G (p.Ile373Ser) and a large deletion ranging from exon 8 to 16 through targeted exome sequencing and microarray analysis. This is the first Korean case of SCOT deficiency caused by novel mutations in OXCT1, resulting in life-threatening ketoacidosis. In patients with unexplained episodic ketosis, or high anion gap metabolic acidosis in infancy, an inherited disorder in ketone body metabolism should be suspected.
Acid-Base Equilibrium ; Acidosis ; Blood Glucose ; Exome ; Exons ; Female ; Humans ; Infant ; Ketone Bodies ; Ketosis ; Metabolism ; Microarray Analysis ; Renal Replacement Therapy ; Transferases

Sodium-glucose cotransporter 2 inhibitors are antidiabetic drugs that increase urinary glucose excretion by inhibiting proximal tubular reabsorption of glucose in the kidney. Some sodium-glucose cotransporter 2 inhibitors have been shown to afford effective glycemic control and to decrease the risks of major adverse cardiovascular events. However, these drugs may increase the risk of diabetic ketoacidosis. This is a rare complication that occurs in less than 0.1% of treated patients with type 2 diabetes. The condition may be euglycemic, and is triggered by controllable precipitating factors such as surgery, infection, and insulin reduction or omission. It is important to understand individual patient profiles and to prevent diabetic ketoacidosis by appropriate prescribing, by withholding sodium-glucose cotransporter 2 inhibitors when indicated, and by counseling patients on sick day management.
Counseling ; Diabetic Ketoacidosis ; Glucose ; Humans ; Hypoglycemic Agents ; Insulin ; Ketone Bodies ; Ketosis* ; Kidney ; Precipitating Factors ; Sick Leave ; Sodium-Glucose Transporter 2

In this study, the Autokit Total Ketone Bodies kit (Wako Pure Chemical, Japan), a total ketone measurement assay using an enzymatic method, was evaluated using a Roche Cobas e702 instrument (Roche Diagnostics, Germany). Precision, linearity, carryover, and reference range verification were evaluated with reference to Clinical Laboratory Standards Institute guidelines. Standard materials provided by the manufacturer and patient samples were used for the evaluation. The precision and carryover of the evaluation result satisfied the acceptance criteria. Linearity was also acceptable at more than 0.99. The quantitative Autokit Total Ketone Bodies kit is precise, and can be widely used in clinical laboratories.
3-Hydroxybutyric Acid ; Evaluation Studies as Topic ; Humans ; Ketone Bodies* ; Methods ; Reference Values

Sodium glucose cotransporter 2 (SGLT2) inhibitor has been recently reported of diabetic ketoacidosis due to accumulation of ketone bodies in patients with severe dehydration caused from such like diarrhea even though the patient had normal glucose level. This is a case of ketoacidosis in normal glucose level as production of ketone bodies is stimulated in liver with increased secretion of glucagon by stimulation of α cells in pancreas due to increase of lipolysis caused from reducing insulin and by SGLT2 inhibitor among patients who are under concurrent insulin and SGLT2 inhibitor. Thus, insulin dosage reduction requires caution in order to control blood glucose level on combined treatment of SGLT2 inhibitor in a patient who is administering insulin because the patient may be caused ketoacidosis in normal blood glucose level.
Blood Glucose ; Dehydration ; Diabetic Ketoacidosis* ; Diarrhea ; Glucagon ; Glucose* ; Humans ; Insulin* ; Ketone Bodies ; Ketosis ; Lipolysis ; Liver ; Pancreas ; Sodium*

Fulminant type 1 diabetes mellitus (FT1DM) is a clinical entity in which the process of beta-cell destruction and subsequent progression of hyperglycemia and ketoacidosis are extremely rapid. A 34-year-old woman without any known risk factor for diabetes mellitus experienced a sudden stillbirth at 30 weeks of gestation. She had normal oral glucose tolerance test during pregnancy. Her blood glucose level was 974 mg/dL. Her urine test for ketone bodies was positive. Her hemoglobin A1c level (6.8%) was near normal range at the first emergency room visit. These findings suggested a very recent onset of diabetes mellitus. Her serum C-peptide level was very low. Islet-related autoantibodies were undetectable. Her clinical course, biochemical, and immunological profiles were consistent with FT1DM. After fluid and insulin based management, beta-cell was rescued with insulin therapy during the evolution of FT1D. At 10 days after admission, maintenance dose of insulin was just 8 unit of insulin once daily. This is the first case of FT1DM with robust recovery in insulin secretion in a pregnant woman who had an initial manifestation of 3rd-trimester intrauterine fetal death in Korea.
Adult ; Autoantibodies ; Blood Glucose ; C-Peptide ; Diabetes Mellitus ; Diabetes Mellitus, Type 1 ; Emergency Service, Hospital ; Female ; Fetal Death* ; Glucose Tolerance Test ; Humans ; Hyperglycemia ; Insulin* ; Ketone Bodies ; Ketosis ; Korea ; Pregnancy ; Pregnant Women* ; Reference Values ; Risk Factors ; Stillbirth

Congenital hyperinsulinism (CHI) is a rare condition that can cause irreversible brain damage during the neonatal period owing to the associated hypoglycemia. Hypoglycemia in CHI occurs secondary to the dysregulation of insulin secretion. CHI has been established as a genetic disorder of islet-cell hyperplasia, associated with a mutation of the ABCC8 or KCNJ11 genes, which encode the sulfonylurea receptor 1 and the inward rectifying potassium channel (Kir6.2) subunit of the ATP-sensitive potassium channel, respectively. We report the case of a female newborn infant who presented with repetitive seizures and episodes of apnea after birth, because of hypoglycemia. Investigations revealed hypoglycemia with hyperinsulinemia, but no ketone bodies, and a low level of free fatty acids. High dose glucose infusion, enteral feeding, and medications could not maintain the patient's serum glucose level. Genetic testing revealed a new variation of ABCC8 mutation. Therefore, we report this case of CHI caused by a novel mutation of ABCC8 in a half-Korean newborn infant with diazoxide-unresponsive hyperinsulinemic hypoglycemia.
Apnea ; Blood Glucose ; Brain ; Congenital Hyperinsulinism* ; Enteral Nutrition ; Fatty Acids, Nonesterified ; Female ; Genetic Testing ; Glucose ; Humans ; Hyperinsulinism ; Hyperplasia ; Hypoglycemia ; Infant, Newborn ; Insulin ; Ketone Bodies ; Parturition ; Potassium Channels ; Seizures

BACKGROUND: Diabetes mellitus and alcohol consumption are the most common causes of ketoacidosis in adults. Recently, beta-hydroxybutyric acid (betaHBA) was reported to be a potential serum biomarker in the diagnosis and monitoring of ketoacidosis. We evaluated the performance of T-KB-H and 3-HB kits for the measurement of ketone bodies [acetoacetate (AcAc)+betaHBA] and betaHBA, respectively. METHODS: Quantitative enzymatic assays were performed using the T-KB-H and 3-HB kits (Nittobo Medical Co., Japan) and the Architect ci16200 Integrated System (Abbott Laboratories, USA). Simultaneously, the ketone body levels in these serum samples were determined by gas chromatography-mas spectrometry (GC-MS). We evaluated precision and linearity of these kits and correlation with GC-MS, and established reference intervals in children and adults. RESULTS: The coefficients of variation for the T-KB-H and 3-HB kits were less than 4.0% at analyte levels of 50, 100, and 400 micromol/L. Linearity was observed for AcAc and betaHBA over a 0-1,000 micromol/L range (R2<0.99). Results from the T-KB-H and 3-HB kits were in good agreement with those from the GC-MS analysis, with correlation coefficients of 0.94 for AcAc and 0.96 for betaHBA. Reference intervals determined for the T-KB-H kit were 9.8-270.1 micromol/L and 18.5-531.8 micromol/L in children and adults, respectively. For the 3-HB kit, the reference intervals were 6.4-234.0 micromol/L and 16.0-437.2 micromol/L in children and adults, respectively. CONCLUSIONS: The T-KB-H and 3-HB kits displayed good precision, clinically acceptable linearity, and reliable correlation with an established assay. This indicates that the kits can be used clinically for measuring serum ketone bodies.
3-Hydroxybutyric Acid* ; Adult ; Alcohol Drinking ; Child ; Diabetes Mellitus ; Diabetic Ketoacidosis ; Diagnosis ; Enzyme Assays ; Gas Chromatography-Mass Spectrometry ; Humans ; Ketone Bodies ; Ketosis ; Spectrum Analysis