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The Journal of Clinical Investigation Oct 1967Catheterization of cerebral vessels in three obese patients undergoing 5-6 wk of starvation demonstrated that beta-hydroxybutyrate and acetoacetate replaced glucose as...
Catheterization of cerebral vessels in three obese patients undergoing 5-6 wk of starvation demonstrated that beta-hydroxybutyrate and acetoacetate replaced glucose as the predominant fuel for brain metabolism. A strikingly low respiratory quotient was also observed, suggesting a carboxylation mechanism as a means of disposing of some of the carbon of the consumed substrates.
Topics: Acetoacetates; Adult; Blood Flow Velocity; Brain; Calorimetry; Catheterization; Female; Glucose; Humans; Hydroxybutyrates; Male; Middle Aged; Starvation
PubMed: 6061736
DOI: 10.1172/JCI105650 -
International Journal of Environmental... Aug 2016A complication of diabetes is diabetic ketoacidosis (DKA), which if left untreated is a life threatening condition. Prompt and accurate diagnosis of DKA is required for... (Review)
Review
A complication of diabetes is diabetic ketoacidosis (DKA), which if left untreated is a life threatening condition. Prompt and accurate diagnosis of DKA is required for the commencement of life saving interventions. Measurements of ketone bodies in DKA have usually been through nitroprusside urine acetoacetate testing. The aim of this systematic review was to examine whether capillary β-hydroxybutyrate (β-OHB) testing is more accurate compared to other diagnostic methods of DKA. The following electronic databases were searched: EBSCO Host, MEDLINE, PSYCHInfo, CINAHL and Science Direct for publications from 1 January 2005 and up to and including 1 January 2016. Inclusion criteria were: Adults 18 years and over and known type 1 or type 2 diabetes. Retrospective and prospective observation studies were included. A total of nine studies met the inclusion criteria. Capillary β-OHB was found to have high sensitivity, specificity, positive predictive value and negative predictive value in identifying DKA compared to urinary ketone testing.
Topics: 3-Hydroxybutyric Acid; Acetoacetates; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Female; Humans; Male; Middle Aged; Prospective Studies; Reagent Kits, Diagnostic; Retrospective Studies; Sensitivity and Specificity
PubMed: 27563914
DOI: 10.3390/ijerph13090837 -
The Journal of Biological Chemistry May 2011Anaplerosis, the net synthesis in mitochondria of citric acid cycle intermediates, and cataplerosis, their export to the cytosol, have been shown to be important for...
Differences between human and rodent pancreatic islets: low pyruvate carboxylase, atp citrate lyase, and pyruvate carboxylation and high glucose-stimulated acetoacetate in human pancreatic islets.
Anaplerosis, the net synthesis in mitochondria of citric acid cycle intermediates, and cataplerosis, their export to the cytosol, have been shown to be important for insulin secretion in rodent beta cells. However, human islets may be different. We observed that the enzyme activity, protein level, and relative mRNA level of the key anaplerotic enzyme pyruvate carboxylase (PC) were 80-90% lower in human pancreatic islets compared with islets of rats and mice and the rat insulinoma cell line INS-1 832/13. Activity and protein of ATP citrate lyase, which uses anaplerotic products in the cytosol, were 60-75% lower in human islets than in rodent islets or the cell line. In line with the lower PC, the percentage of glucose-derived pyruvate that entered mitochondrial metabolism via carboxylation in human islets was only 20-30% that in rat islets. This suggests human islets depend less on pyruvate carboxylation than rodent models that were used to establish the role of PC in insulin secretion. Human islets possessed high levels of succinyl-CoA:3-ketoacid-CoA transferase, an enzyme that forms acetoacetate in the mitochondria, and acetoacetyl-CoA synthetase, which uses acetoacetate to form acyl-CoAs in the cytosol. Glucose-stimulated human islets released insulin similarly to rat islets but formed much more acetoacetate. β-Hydroxybutyrate augmented insulin secretion in human islets. This information supports previous data that indicate beta cells can use a pathway involving succinyl-CoA:3-ketoacid-CoA transferase and acetoacetyl-CoA synthetase to synthesize and use acetoacetate and suggests human islets may use this pathway more than PC and citrate to form cytosolic acyl-CoAs.
Topics: ATP Citrate (pro-S)-Lyase; Acetoacetates; Animals; Cell Line, Tumor; Glucose; Humans; Islets of Langerhans; Mice; Pyruvate Carboxylase; Pyruvic Acid; Rats; Rats, Sprague-Dawley; Species Specificity; Sweetening Agents
PubMed: 21454710
DOI: 10.1074/jbc.M111.241182 -
Journal of Photochemistry and... Oct 2016Amadori product is an important and stable intermediate, which is produced during glycation process. It is a marker of hyperglycemia in diabetes mellitus, and its...
Amadori product is an important and stable intermediate, which is produced during glycation process. It is a marker of hyperglycemia in diabetes mellitus, and its accumulation in the body contributes to microvascular complication of diabetes including diabetic nephropathy and retinopathy. In this study, the effect of acetoacetate on the formation of Amadori products and biophysical properties of human serum albumin (HSA), after incubation with glucose, was investigated using various methods. These included circular dichroism (CD), Fourier transform infrared (FTIR) spectroscopy, and UV-visible and fluorescence spectroscopy. Our results indicated that the production of Amadori products in HSA incubated with glucose (GHSA) was increased in the presence of acetoacetate. We also detected alterations in the secondary and tertiary structure of GHSA, which was increased in the presence of acetoacetate. These changes were attributed to the formation of covalent bonds between the carbonyl group of acetoacetate and the nucleophilic groups (lysine residues) of HSA. Thus, acetoacetate can enhance the production of Amadori products through formation of covalent bonds with biomaterials.
Topics: Acetoacetates; Glucose; Glycosylation; Humans; Protein Structure, Secondary; Serum Albumin
PubMed: 27614245
DOI: 10.1016/j.jphotobiol.2016.09.004 -
The Journal of Clinical Investigation Nov 1970Transport of free fatty acids from the blood into the splanchnic region and their conversion to triglycerides of very low density lipoproteins, together with estimates...
Transport of free fatty acids from the blood into the splanchnic region and their conversion to triglycerides of very low density lipoproteins, together with estimates of splanchnic oxidation of free fatty acids to ketones and to carbon dioxide and water, have been made in the postabsorptive state in seven normolipemic subjects, six with primary endogenous hyperlipemia and one each with primary dysbetalipoproteinemia and mixed hyperlipemia. Net systemic transport of free fatty acids into the blood was the same in normolipemic and hyperlipemic groups, but a greater fraction was taken up in the splanchnic region in the latter. Transport into the blood in very low density lipoproteins of triglyceride fatty acids derived from free fatty acids was proportional and bore the same relationship to splanchnic uptake of free fatty acids in the two groups. In normolipemic subjects, near equilibration of specific activities after 4 hr infusion of palmitate-1-(14)C showed that almost all triglyceride fatty acids of very low density lipoproteins and acetoacetate were derived from free fatty acids taken up in the splanchnic region. In the hyperlipemic subjects, equilibration of free fatty acidcarbon with acetoacetate was almost complete, but not with triglyceride fatty acids, owing at least in part to increased pool size. Comparison of the rate of equilibration of triglyceride fatty acids-(14)C with rate of inflow transport from the splanchnic region, together with other data, indicated that most of the circulating triglyceride fatty acids of very low density lipoproteins in hyperlipemic subjects were also derived from free fatty acids. Although mean inflow transport of triglyceride fatty acids was greater in the hyperlipemic subjects, it correlated poorly with their concentration and it appeared that efficiency of mechanisms for extrahepatic removal must be a major determinant of the concentration of triglycerides in blood plasma of the normolipemic as well as the hyperlipemic subjects. Estimates of splanchnic respiratory quotient supported the concept that oxidation of free fatty acids accounts for almost all of splanchnic oxygen consumption in the postabsorptive state. Splanchnic oxygen consumption was greater in the hyperlipemics, but fractional oxidation of free fatty acids to ketones was higher in normolipemic subjects. Calculations of splanchnic balance indicate that a larger fraction of free fatty acids was stored in lipids of splanchnic tissues in the hyperlipemics. No differences were found between the two groups in net splanchnic transport of glucose, lactate, or glycerol.
Topics: Acetoacetates; Adult; Biological Transport; Body Weight; Carbohydrate Metabolism; Fatty Acids, Nonesterified; Female; Humans; Hydroxybutyrates; Hyperlipidemias; Intestinal Mucosa; Ketones; Lipoproteins; Liver; Male; Methods; Middle Aged; Oxygen Consumption; Plasma Volume; Triglycerides
PubMed: 5475985
DOI: 10.1172/JCI106422 -
British Medical Journal Oct 1970
Topics: Acetoacetates; Diabetic Ketoacidosis; Humans; Methods
PubMed: 4990549
DOI: 10.1136/bmj.4.5727.116-b -
Cell Metabolism Feb 2019Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we...
Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[C]β-hydroxybutyrate (D-βOHB) labeled almost none. [C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.
Topics: 3-Hydroxybutyric Acid; Acetoacetates; Animals; Hepatocytes; Liver Cirrhosis, Experimental; Macrophages; Mice; Mice, Inbred C57BL; Mitochondria
PubMed: 30449686
DOI: 10.1016/j.cmet.2018.10.015 -
The Biochemical Journal Nov 1969Insulin was treated with diketen at pH6.9. The reaction mixture was resolved into four components by DEAE-Sephadex chromatography. The first component was unchanged...
Insulin was treated with diketen at pH6.9. The reaction mixture was resolved into four components by DEAE-Sephadex chromatography. The first component was unchanged insulin. The second and third components were shown by end-group analysis to be substituted on phenylalanine B-1 and glycine A-1 respectively. The fourth component was disubstituted on both phenylalanine B-1 and glycine A-1. The in-amino group of lysine B-29 was not involved in the reaction at low reagent concentrations. The purity of these derivatives was checked by their electrophoretic behaviour and by measurement of the rate of their reaction with trinitrobenzenesulphonic acid. The hormonal activity of the derivatives was determined. The effect of the modifications on the hormonal activity and the tertiary structure of insulin is discussed.
Topics: Acetoacetates; Animals; Biological Assay; Chemical Phenomena; Chemistry; Chromatography; Electrophoresis; Glycine; Heterocyclic Compounds; Insulin; Lactones; Lysine; Mice; Nitrobenzenes; Phenylalanine; Sulfonic Acids
PubMed: 5353531
DOI: 10.1042/bj1150587 -
The Journal of Biological Chemistry May 20222-Ketopropyl-coenzyme M oxidoreductase/carboxylase (2-KPCC) is a member of the flavin and cysteine disulfide containing oxidoreductase family (DSOR) that catalyzes the...
2-Ketopropyl-coenzyme M oxidoreductase/carboxylase (2-KPCC) is a member of the flavin and cysteine disulfide containing oxidoreductase family (DSOR) that catalyzes the unique reaction between atmospheric CO and a ketone/enolate nucleophile to generate acetoacetate. However, the mechanism of this reaction is not well understood. Here, we present evidence that 2-KPCC, in contrast to the well-characterized DSOR enzyme glutathione reductase, undergoes conformational changes during catalysis. Using a suite of biophysical techniques including limited proteolysis, differential scanning fluorimetry, and native mass spectrometry in the presence of substrates and inhibitors, we observed conformational differences between different ligand-bound 2-KPCC species within the catalytic cycle. Analysis of site-specific amino acid variants indicated that 2-KPCC-defining residues, Phe501-His506, within the active site are important for transducing these ligand induced conformational changes. We propose that these conformational changes promote substrate discrimination between H and CO to favor the metabolically preferred carboxylation product, acetoacetate.
Topics: Acetoacetates; Carbon Dioxide; Carboxy-Lyases; Catalysis; Ligands; Mesna; Oxidoreductases; Xanthobacter
PubMed: 35367206
DOI: 10.1016/j.jbc.2022.101884 -
The Journal of Clinical Investigation Feb 1974Rates of plasma acetoacetate and total ketone-body production and oxidation to CO2 were determined by an isotope tracer technique in eight obese subjects undergoing...
Rates of plasma acetoacetate and total ketone-body production and oxidation to CO2 were determined by an isotope tracer technique in eight obese subjects undergoing progressive starvation. After a brief fast and under conditions of mild ketonemia and minimal ketonuria, rates of acetoacetate and total ketone-body production and oxidation were directly related to the increasing plasma concentration. After a longer fast and with severer ketonemia, acetoacetate and total ketone-body production and oxidation rates were higher but became constant and unrelated to the plasma concentrations. The maximum rates of total ketone-body production and oxidation were about 150 g/24 h and 129 g/24 h, respectively. Although an increased ketone-body production was the primary factor responsible for the hyperketonemia, an imbalance between production and removal of the ketone bodies cannot be excluded. Such an imbalance could account, at least in part, for the developing hyperketonemia and for the lack of relationship between production rates and plasma concentrations.
Topics: Acetoacetates; Adult; Aged; Blood Glucose; Fasting; Female; Humans; Ketone Bodies; Male; Middle Aged; Obesity; Oxidation-Reduction
PubMed: 11344564
DOI: 10.1172/JCI107584