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2.
Life Sci ; 253: 117748, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32387415

RESUMO

AIMS: Hindlimb ischemia-reperfusion (IR) was previously demonstrated by our group to decrease blood sugar levels by suppressing hepatic gluconeogenesis and enhancing glucose uptake using activation of the parasympathetic nervous system. While IR attenuated hyperglycemia in diabetic mice, it was unclear whether IR regulated energy metabolism in the liver. We investigated the mechanisms by which IR regulates energy metabolism in the liver from type1 diabetic mice. MAIN METHODS: Streptozotocin-induced diabetic male C57BL/6J mice were used to determine the effect of IR on the factors involved in energy metabolism in the liver (i.e., activation levels of AMP-activated protein kinase, aconitase and pyruvate dehydrogenase; adenosine triphosphate and fumarate concentrations; sirtuin (Sirt) 1 expression). These various signaling pathways and key enzyme activities were examined using western blot analysis and a biochemical technique including a colorimetric assay. KEY FINDINGS: Under feeding conditions (free access to normal murine chow and water), blood glucose levels and serum ketone body levels were significantly suppressed by IR, whereas phospho-AMP-activated protein kinase and its activity, pyruvate dehydrogenase, aconitase activity, and Sirt 1expression were upregulated. In contrast, peroxisome proliferator-activated receptor γ coactivator-1, which accelerated fatty acid use, was suppressed by IR. SIGNIFICANCE: These results indicated that in the IR-treated diabetic liver, energy production was promoted through acceleration of the tricarboxylic acid cycle linked with increased glucose preference rather than fatty acid under feeding conditions. Therefore, IR may be beneficial against diabetic hyperglycemia, but also ketoacidosis.


Assuntos
Diabetes Mellitus Experimental/complicações , Cetoacidose Diabética/prevenção & controle , Precondicionamento Isquêmico , Fígado/metabolismo , Animais , Glicemia/metabolismo , Ciclo do Ácido Cítrico/fisiologia , Metabolismo Energético/fisiologia , Ácidos Graxos/metabolismo , Glicólise/fisiologia , Corpos Cetônicos/sangue , Fígado/irrigação sanguínea , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estreptozocina
3.
PLoS One ; 15(3): e0229868, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32163448

RESUMO

The purpose of this study was to examine the influence of medium-chain fatty acid-containing triglycerides (MCT), long-chain polyunsaturated fatty acid-containing triglycerides, and their combination on the plasma metabolome of cats (Felis catus), including circulating microbiome-derived postbiotics. After a 14-day lead-in on the control food, cats were randomized to one of four foods (control, with 6.9% MCT, with fish oil [FO; 0.14% eicosapentaenoate, 1.0% docosahexaenoate], or with FO+MCT; n = 16 per group) for 28 days. Analysis of plasma metabolites showed that the addition of FO and MCT led to synergistic effects not seen with either alone across a number of lipid classes, including fatty acids, acylcarnitines, and acylated amines including endocannabinoids. Notably, the FO+MCT group had an increase in ketone body production relative to baseline and beyond that seen with MCT alone. N-acyl taurines, the accumulation of which has been implicated in the onset of type 2 diabetes, were significantly decreased in the FO+MCT group. Significant decreases in the gut microbiome-derived postbiotic classes of indoles/indolic sulfates and phenols/phenolic sulfates were observed only the FO+MCT group. Overall, the combination of MCT and FO led to number of changes in plasma metabolites that were not observed with either oil alone, particularly in postbiotics.


Assuntos
Ração Animal , Ácidos Docosa-Hexaenoicos/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Triglicerídeos/administração & dosagem , Animais , Gatos , Feminino , Indóis/sangue , Indóis/metabolismo , Corpos Cetônicos/sangue , Corpos Cetônicos/metabolismo , Lipidômica , Lipídeos/sangue , Masculino , Fenóis/sangue , Fenóis/metabolismo
4.
Arterioscler Thromb Vasc Biol ; 39(4): 665-674, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30816800

RESUMO

Objective- Loss-of-function (LOF) variants in the ANGPTL3 (angiopoietin-like protein 3) have been associated with low levels of plasma lipoproteins and decreased coronary artery disease risk. We aimed to determine detailed metabolic effects of genetically induced ANGPTL3 deficiency in fasting and postprandial state. Approach and Results- We studied individuals carrying S17X LOF mutation in ANGPTL3 (6 homozygous and 32 heterozygous carriers) and 38 noncarriers. Nuclear magnetic resonance metabolomics was used to quantify 225 circulating metabolic measures. We compared metabolic differences between LOF carriers and noncarriers in fasting state and after a high-fat meal. In fasting, ANGPTL3 deficiency was characterized by similar extent of reductions in LDL (low-density lipoprotein) cholesterol (0.74 SD units lower concentration per LOF allele [95% CI, 0.42-1.06]) as observed for many TRL (triglyceride-rich lipoprotein) measures, including VLDL (very-low-density lipoprotein) cholesterol (0.75 [95% CI, 0.45-1.05]). Within most lipoprotein subclasses, absolute levels of cholesterol were decreased more than triglycerides, resulting in the relative proportion of cholesterol being reduced within TRLs and their remnants. Further, ß-hydroxybutyrate was elevated (0.55 [95% CI, 0.21-0.89]). Homozygous ANGPTL3 LOF carriers showed essentially no postprandial increase in TRLs and fatty acids, without evidence for adverse compensatory metabolic effects. Conclusions- In addition to overall triglyceride- and LDL cholesterol-lowering effects, ANGPTL3 deficiency results in reduction of cholesterol proportion within TRLs and their remnants. Further, ANGPTL3 LOF carriers had elevated ketone body production, suggesting enhanced hepatic fatty acid ß-oxidation. The detailed metabolic profile in human knockouts of ANGPTL3 reinforces inactivation of ANGPTL3 as a promising therapeutic target for decreasing cardiovascular risk.


Assuntos
Proteínas Semelhantes a Angiopoietina/deficiência , Jejum/sangue , Lipoproteínas/sangue , Metaboloma , Período Pós-Prandial , Adulto , Alelos , Proteínas Semelhantes a Angiopoietina/genética , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Gorduras na Dieta , Feminino , Genótipo , Humanos , Corpos Cetônicos/sangue , Fígado/metabolismo , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Triglicerídeos/sangue
5.
Yonsei Med J ; 60(3): 308-311, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30799594

RESUMO

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.


Assuntos
Acidose/genética , Coenzima A-Transferases/deficiência , Cetose/etiologia , Mutação/genética , Sequência de Bases , Coenzima A-Transferases/genética , Éxons/genética , Feminino , Heterozigoto , Humanos , Lactente , Corpos Cetônicos/sangue , Corpos Cetônicos/urina
6.
Int J Food Sci Nutr ; 70(7): 834-844, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30764676

RESUMO

The aim of this study was to examine the effects of α-lipoic acid (α-LA) on liver mitochondrial bioenergetics and oxidative status for 8 weeks in normal-healthy animals. A pair-fed group was included to differentiate between α-LA direct effects and those changes due to reduced food intake. α-LA decreased body weight gain, liver weight and insulin levels with no differences compared to its pair-fed group. α-LA significantly reduced energy efficiency, the activity of the electron transport chain complexes and induced a lower efficiency of oxidative phosphorylation with reduced ATP production. α-LA supplementation directly decreased plasma triglycerides (TGs), free fatty acids and ketone bodies levels. A significant reduction in hepatic TG content was also observed. A significant up-regulation of Cpt1a, Acadl and Sirt3, all ß-oxidation genes, along with a significant deacetylation of the forkhead transcription factor 3a (FOXO3A) was found in α-LA-treated animals. Thus, α-LA along with a standard chow diet has direct actions on lipid metabolism and liver by modulating mitochondrial function in normal-weight rats. These results should be taken into account when α-LA is administered or recommended to a healthy population.


Assuntos
Carnitina O-Palmitoiltransferase/metabolismo , Metabolismo Energético , Proteína Forkhead Box O3/metabolismo , Fígado/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Sirtuínas/metabolismo , Ácido Tióctico/farmacologia , Animais , Glicemia , Carnitina O-Palmitoiltransferase/genética , Ácidos Graxos não Esterificados/sangue , Proteína Forkhead Box O3/genética , Corpos Cetônicos/sangue , Metabolismo dos Lipídeos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Mitocôndrias/metabolismo , Fosforilação , Ratos , Ratos Wistar , Sirtuínas/genética , Triglicerídeos/sangue , Regulação para Cima
7.
Neurosci Lett ; 690: 232-236, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30367958

RESUMO

Clinical and animal studies suggested that a medium-chain triglyceride (MCT)-based ketogenic diet provides an alternative energy substrate to the brain and has neuroprotective effects, but the clinical evidence is still scarce. Here we examined the effect of an MCT-based ketogenic formula on cognitive function in patients with Alzheimer's disease (AD). The subjects were 20 Japanese patients with mild-to-moderate AD (11 males, nine females, mean age 73.4 ± 6.0 years) who, on separate days, underwent neurocognitive tests 120 min after consuming 50 g of a ketogenic formula (Ketonformula®) containing 20 g of MCTs or an isocaloric placebo formula without MCTs. The patients then took 50 g of the ketogenic formula daily for up to 12 weeks, and underwent neurocognitive tests monthly. In the first trial, although the patients' plasma levels of ketone bodies were successfully increased 120 min after the single intake of the ketogenic formula, there was no significant difference in any cognitive test results between the administrations of the ketogenic and placebo formulae. In the subsequent chronic intake trial of the ketogenic formula, 16 of the 20 patients completed the 12-week regimen. At 8 weeks after the trial's start, the patients showed significant improvement in their immediate and delayed logical memory tests compared to their baseline scores, and at 12 weeks they showed significant improvements in the digit-symbol coding test and immediate logical memory test compared to the baseline. The chronic consumption of the ketogenic formula was therefore suggested to have positive effects on verbal memory and processing speed in patients with AD.


Assuntos
Doença de Alzheimer/dietoterapia , Doença de Alzheimer/psicologia , Cognição/efeitos dos fármacos , Dieta Cetogênica , Triglicerídeos/química , Triglicerídeos/uso terapêutico , Idoso , Doença de Alzheimer/sangue , Método Duplo-Cego , Feminino , Humanos , Corpos Cetônicos/sangue , Masculino , Testes Neuropsicológicos
8.
Circ Heart Fail ; 11(12): e004953, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30562098

RESUMO

BACKGROUND: Deranged energy metabolism contributes to the pathophysiology of heart failure (HF). Recent studies showed diminished free fatty acid (FFA) oxidation in experimental HF models with a shift towards oxidation of ketone bodies. However, conflicting clinical data on FFA metabolism and limited knowledge on ketone body metabolism in human HF mandate additional metabolic profiling studies. We, therefore, investigated cardiac uptake of FFAs and ketone bodies (ß-hydroxybutyrate and acetoacetate) in patients with HF with reduced ejection fraction (HFrEF) or with aortic stenosis (AS)-induced left ventricular hypertrophy. We hypothesized that FFA oxidation is impaired in HFrEF and in AS and results in decreased concentrations of free carnitine, the necessary carrier for mitochondrial entry of activated FFAs, and in accumulation of metabolic intermediates. METHODS AND RESULTS: We collected arterial and coronary sinus blood samples in patients with HFrEF (n=15), in AS patients with preserved systolic function (n=15), and in control patients (n=15). Plasma concentration gradients across the heart show significantly greater uptake of ketone bodies in patients with HFrEF than in controls. Patients with AS show significantly increased uptake of ß-hydroxybutyrate and FFAs. Free carnitine concentration and concentration gradients of intermediates of FFA oxidation were comparable between groups. CONCLUSIONS: In conclusion, our results show significantly increased cardiac uptake of ketone bodies in patients with stable HFrEF and AS and increased uptake of FFAs in AS compared with control patients. The lack of myocardial release of acyl-carnitine species or change in free carnitine uptake suggests no impairment of FFA oxidation.


Assuntos
Estenose da Valva Aórtica/sangue , Metabolismo Energético , Ácidos Graxos não Esterificados/sangue , Insuficiência Cardíaca/sangue , Hipertrofia Ventricular Esquerda/sangue , Corpos Cetônicos/sangue , Miocárdio/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Ácido 3-Hidroxibutírico/sangue , Adaptação Fisiológica , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/diagnóstico , Estenose da Valva Aórtica/fisiopatologia , Biomarcadores/sangue , Carnitina/sangue , Estudos de Casos e Controles , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Oxirredução , Volume Sistólico
9.
Anaesth Intensive Care ; 46(5): 463-467, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30189819

RESUMO

Prolonged fasting leads to a shift from carbohydrate to fat as the primary energy source, resulting in the production of ketones such as beta-hydroxybutyrate. Hyperketonaemia and ketoacidosis have been observed in young children fasting for surgery. The aim of this study was to investigate ketonaemia in adults fasted for surgery. One hundred non-diabetic adults presenting for elective or emergency surgery were assessed for the presence of hyperketonaemia (beta-hydroxybutyrate levels more than 1 mmol/l), and the relationship between beta-hydroxybutyrate, blood glucose and fasting duration was investigated. Three of 100 patients demonstrated hyperketonaemia, one of whom had ingested a ketogenic supplement the evening prior to surgery. No patient demonstrated beta-hydroxybutyrate levels suggestive of ketoacidosis (above 3 mmol/l). No relationship between fasting duration and ketone or glucose levels was observed. We found no evidence that prolonged preoperative fasting led to beta-hydroxybutyrate levels consistent with ketoacidosis.


Assuntos
Jejum , Corpos Cetônicos/sangue , Cuidados Pré-Operatórios , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos Eletivos , Emergências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Centros de Atenção Terciária , Adulto Jovem
10.
J Clin Endocrinol Metab ; 103(12): 4569-4579, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30113659

RESUMO

Objective: We studied whether blood metabolomic measures in people with type 2 diabetes (T2D) are associated with insufficient glycemic control and whether this association is influenced differentially by various diabetes drugs. We then tested whether the same metabolomic profiles were associated with the initiation of insulin therapy. Methods: A total of 162 metabolomic measures were analyzed using a nuclear magnetic resonance-based method in people with T2D from four cohort studies (n = 2641) and one replication cohort (n = 395). Linear and logistic regression analyses with adjustment for potential confounders, followed by meta-analyses, were performed to analyze associations with hemoglobin A1c levels, six glucose-lowering drug categories, and insulin initiation during a 7-year follow-up period (n = 698). Results: After Bonferroni correction, 26 measures were associated with insufficient glycemic control (HbA1c >53 mmol/mol). The strongest association was with glutamine (OR, 0.66; 95% CI, 0.61 to 0.73; P = 7.6 × 10-19). In addition, compared with treatment-naive patients, 31 metabolomic measures were associated with glucose-lowering drug use (representing various metabolite categories; P ≤ 3.1 × 10-4 for all). In drug-stratified analyses, associations with insufficient glycemic control were only mildly affected by different glucose-lowering drugs. Five of the 26 metabolomic measures (apolipoprotein A1 and medium high-density lipoprotein subclasses) were also associated with insulin initiation during follow-up in both discovery and replication. The strongest association was observed for medium high-density lipoprotein cholesteryl ester (OR, 0.54; 95% CI, 0.42 to 0.71; P = 4.5 × 10-6). Conclusion: Blood metabolomic measures were associated with present and future glycemic control and might thus provide relevant cues to identify those at increased risk of treatment failure.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Metabolômica/métodos , Idoso , Aminoácidos/sangue , Aminoácidos/metabolismo , Apolipoproteína A-I/sangue , Apolipoproteína A-I/metabolismo , Glicemia/análise , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Progressão da Doença , Ácidos Graxos/sangue , Ácidos Graxos/metabolismo , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Corpos Cetônicos/sangue , Corpos Cetônicos/metabolismo , Lipoproteínas HDL/sangue , Lipoproteínas HDL/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Falha de Tratamento
11.
Diabetes Obes Metab ; 20(11): 2515-2522, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30073768

RESUMO

Recent clinical trials have demonstrated a strong cardiovascular (CV) protective effect of sodium/glucose cotransporter (SGLT) 2 inhibitors, a recently introduced class of hypoglycaemic agents. The improvement in glycated haemoglobin and other conventional risk factors explains only a portion of the observed reduction in CV risk. A relevant feature of SGLT2-inhibitor-treated diabetic patients is the increase in circulating levels of ketone bodies, which has been proposed to mediate part of the beneficial effects of this class of drugs, mainly through their bioenergetic properties. However, ketone bodies are emerging as potent anti-inflammatory molecules, and inflammation is a recognized risk factor for the development of CV events. In this framework, we hypothesize that, through their unique mechanism of action and by increasing circulating ketone bodies, SGLT2 inhibitors indirectly target the IL-1ß pathway and thus produce a consistent amelioration of low-grade inflammation, a clinically relevant phenomenon in diabetic patients with high CV risk. This attenuation could slow the progression of CV disease and especially the atherosclerotic process, which is sensitive to environmental changes, even over a short time period. To test this conceptual structure, it would be necessary to measure circulating pro-inflammatory molecules in patients treated with SGLT inhibitors. The addition of inflammatory markers to the list of clinical data measured in FDA-requested, large CV outcome trials could provide supplementary information regarding potential secondary effects of new anti-hyperglycaemic drugs, considering that the inflammatory process is an often neglected cornerstone of CV diseases.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Inflamação/sangue , Inflamação/complicações , Corpos Cetônicos/sangue , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Doenças Cardiovasculares/sangue , Sistema Cardiovascular/efeitos dos fármacos , Humanos , Inflamação/patologia , Corpos Cetônicos/fisiologia , Fatores de Risco
12.
J. physiol. biochem ; 74(3): 403-416, ago. 2018. graf
Artigo em Inglês | IBECS | ID: ibc-178995

RESUMO

Diabetes mellitus (DM) is a chronic disease that can affect metabolism of glucose and other metabolites. In this study, the normal- and obese-diabetic rats were compared to understand the diabetes disorders of type 1 and 2 diabetes mellitus. This was done by evaluating their urine metabolites using proton nuclear magnetic resonance (1H NMR)-based metabolomics and comparing with controls at different time points, considering the induction periods of obesity and diabetes. The biochemical parameters of the serum were also investigated. The obese-diabetic model was developed by feeding the rats a high-fat diet and inducing diabetic conditions with a low dose of streptozotocin (STZ) (25 mg/kg bw). However, the normal rats were induced by a high dose of STZ (55 mg/kg bw). A partial least squares discriminant analysis (PLS-DA) model showed the biomarkers of both DM types compared to control. The synthesis and degradation of ketone bodies, tricarboxylic (TCA) cycles, and amino acid pathways were the ones most involved in the variation with the highest impact. The diabetic groups also exhibited a noticeable increase in the plasma glucose level and lipid profile disorders compared to the control. There was also an increase in the plasma cholesterol and low-density lipoprotein (LDL) levels and a decline in the high-density lipoprotein (HDL) of diabetic rats. The normal-diabetic rats exhibited the highest effect of all parameters compared to the obese-diabetic rats in the advancement of the DM period. This finding can build a platform to understand the metabolic and biochemical complications of both types of DM and can generate ideas for finding targeted drugs


No disponible


Assuntos
Animais , Masculino , Ratos , Diabetes Mellitus Experimental/sangue , Hipoglicemiantes/farmacologia , Metaboloma , Metformina/farmacologia , Obesidade/sangue , Aminoácidos/sangue , Aminoácidos/urina , Glicemia/metabolismo , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica/efeitos adversos , Corpos Cetônicos/sangue , Ratos Sprague-Dawley
13.
J. physiol. biochem ; 74(3): 417-429, ago. 2018. graf, tab
Artigo em Inglês | IBECS | ID: ibc-178996

RESUMO

Cardiac arrest is one of the leading causes of death among adults in older age. Understanding mechanisms how organism responds to ischemia at global level is essential for the prevention and ischemic patient’s treatment. In this study, we used a global cerebral ischemia induced by four-vessel occlusion as an established animal model for ischemic stroke to investigate metabolic changes after 24 h reperfusion, when transitions occur due to the onset of delayed neuronal death. We also focused on the endogenous phenomenon known as ischemic tolerance by the pre-ischemic treatment. The experiments were carried out on blood plasma samples as easily available and metabolically reflecting the overall changes in injured organism. Our results imply that disturbed glycolysis pathway, as a consequence of ischemic injury, leads to the increased level of ketone bodies (acetone, acetoacetate and β-hydroxybutyrate) along with increased utilization of triacylglycerols in plasma of ischemic and ischemically preconditioned rats. Complementary to, a decreased level of glycolytic intermediates (lactate, pyruvate, acetate) with increased level of glucose was found in ischemic and preconditioned animals. The protective effect of ischemic preconditioning on metabolome recovery was demonstrated by significantly increased level of creatine compared to ischemic, non-preconditioned rats. We also document that acetoacetate, pyruvate, lactate, and leucine have the best discriminatory power between ischemic and control plasma. Conclusively, our results provide evidence that NMR spectra analysis can identify specific group of metabolites present in plasma with the capability for discrimination between individual groups of animals. In addition, an excellent feasibility for the statistical discrimination among ischemic, preconditioned, and control rats can be applied regardless of native or deproteinated plasma and also regardless of noesy or cpmg NMR acquisition


No disponible


Assuntos
Animais , Masculino , Ratos , Isquemia Encefálica/sangue , Transtornos Cerebrovasculares/sangue , Precondicionamento Isquêmico/métodos , Corpos Cetônicos/sangue , Metaboloma , Traumatismo por Reperfusão/sangue , Ácido Acético/sangue , Biomarcadores/sangue , Glicemia/metabolismo , Isquemia Encefálica/patologia , Transtornos Cerebrovasculares/patologia , Creatina/sangue , Traumatismo por Reperfusão/patologia , Triglicerídeos/sangue
14.
Int J Legal Med ; 132(6): 1713-1718, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29974235

RESUMO

Diabetes mellitus (DM) could cause pilot incapacitation and result in aviation fatalities. The mechanisms could be directly as a consequence of acute hypoglycemia/subacute diabetic ketoacidosis (DKA) or indirectly as an acute cardiovascular event by contributing to the development of atherosclerosis in coronary or carotid and cerebral arteries. In this study, DM-related fatal flight accidents in the US National Transport Bureau's database between years 2011-2016 were analyzed with special emphasis on postmortem (PM) glucose levels and correlation of toxicological reports with anamnestic information on DM. Additionally, autopsy results on coronary arteries were reviewed. In 43 out of 1491 (~ 3%) fatal accidents pilots had DM. Postmortem glucose or glycated hemoglobin percentage (Hb1Ac) was measured in 12 of the 43 cases; while antidiabetic medication was found in 14 of the cases (only two of the cases had both glucose measurements and medication). With the increasing prevalence of DM, a possibility of pilot incapacitation due to DM or complications of DM should be actively studied, even if no anamnestic information of DM was available. While PM hypoglycemia is difficult to assess, we propose a systematic investigation based on measurement of glucose, Hb1Ac%, and ketone bodies, and documentation of atherosclerotic lesions in major arteries to identify or rule out DM as a cause of pilot incapacitation.


Assuntos
Acidentes Aeronáuticos/estatística & dados numéricos , Diabetes Mellitus/epidemiologia , Pilotos , Adulto , Idoso , Glicemia/análise , Doença da Artéria Coronariana/patologia , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/sangue , Corpos Cetônicos/sangue , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Corpo Vítreo/metabolismo
15.
Fukushima J Med Sci ; 64(2): 60-63, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30012937

RESUMO

BACKGROUND: Breath acetone is reported to be a noninvasive biomarker for heart failure. However, the measurement of this metabolite requires expertize and is not standardized yet. Acetone is also released from the skin; thus, measuring acetone as a skin gas may be easier than breath analysis. METHODS: We analyzed skin acetone collected from 41 hospitalized patients with cardiovascular diseases. Passive samplers were used to measure skin acetone emission. Passive sampler was softly fixed on the surface of forearm skin for 10 hour at night. RESULTS: Skin acetone emission ranged from 0.00 to 2.70 ng/cm2/h, and was significantly correlated with blood ketone bodies (r = 0.377, p = 0.017). CONCLUSIONS: This is the first study to analyze skin gas in patients with cardiovascular diseases. Skin acetone emission was found to reflect blood ketone bodies. It is feasible to measure skin acetone emission for reflecting blood ketone bodies in patients with cardiovascular diseases.


Assuntos
Acetona/análise , Doenças Cardiovasculares/metabolismo , Pele/química , Adulto , Idoso , Estudos de Viabilidade , Feminino , Humanos , Corpos Cetônicos/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
16.
Cell Physiol Biochem ; 48(3): 1317-1331, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30048968

RESUMO

BACKGROUND/AIMS: Systemic hyperlipidemia and intracellular lipid accumulation induced by chronic high fat diet (HFD) leads to enhanced fatty acid oxidation (FAO) and ketogenesis. The present study was aimed to determine whether activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) by surplus free fatty acids (FA) in hyperlipidemic condition, has a positive feedback regulation over FAO and ketogenic enzymes controlling lipotoxicity and cardiac apoptosis. METHODS: 8 weeks old C57BL/6 wild type (WT) or PPAR-γ-/- mice were challenged with 16 weeks 60% HFD to induce obesity mediated type 2 diabetes mellitus (T2DM) and diabetic cardiomyopathy. Treatment course was followed by echocardiographic measurements, glycemic and lipid profiling, immunoblot, qPCR and immunohistochemistry (IHC) analysis of PPAR-γ and following mitochondrial metabolic enzymes 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2), mitochondrial ß- hydroxy butyrate dehydrogenase (BDH1) and pyruvate dehydrogenase kinase isoform 4 (PDK4). In vivo model was translated in vitro, with neonatal rat cardiomyocytes (NRCM) treated with PPAR-γ agonist/antagonist and PPAR-γ overexpression adenovirus in presence of palmitic acid (PA). Apoptosis was determined in vivo from left ventricular heart by TUNEL assay and immunoblot analysis. RESULTS: We found exaggerated circulating ketone bodies production and expressions of the related mitochondrial enzymes HMGCS2, BDH1 and PDK4 in HFD-induced diabetic hearts and in PA-treated NRCM. As a mechanistic approach we found HFD mediated activation of PPAR-γ is associated with the above-mentioned mitochondrial enzymes. HFD-fed PPAR-γ-/-mice display decreased hyperglycemia, hyperlipidemia associated with increased insulin responsiveness as compared to HFD-fed WT mice PPAR-γ-/-HFD mice demonstrated a more robust functional recovery after diabetes induction, as well as significantly reduced myocyte apoptosis and improved cardiac function. CONCLUSIONS: PPAR-γ has been described previously to regulate lipid metabolism and adipogenesis. The present study suggests for the first time that increased PPAR-γ expression by HFD is responsible for cardiac dysfunction via upregulation of mitochondrial enzymes HMGCS2, BDH1 and PDK4. Targeting PPAR-γ and its downstream mitochondrial enzymes will provide novel strategies in preventing metabolic and myocardial dysfunction in diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Corpos Cetônicos/metabolismo , PPAR gama/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Cardiomiopatias Diabéticas/sangue , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/patologia , Ácidos Graxos/sangue , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Corpos Cetônicos/sangue , Masculino , Camundongos Endogâmicos C57BL , Oxirredução , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/patologia
17.
An Acad Bras Cienc ; 90(2): 1649-1658, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29898113

RESUMO

The aim of this study was to evaluate whether the use of subcutaneous mineral supplementation would affect metabolic parameters, immunological response, milk quality and composition of dairy cows in the postpartum period. Twelve pregnant primiparous Holstein cows, were divided into two groups: six animals supplemented with the mineral complex (magnesium, phosphorus, potassium, selenium and copper), and six animals used as controls. Milk samples were collected every two other weeks postpartum up to sixty days of lactation to analyze composition and quality. Blood samples were collected, and the levels of ketone bodies, total proteins, glucose, albumin, and globulin were measured. The catalase and superoxide enzymes, reactive oxygen species, tumor necrosis factor, and interleukins were determined. Animals supplemented with minerals showed lower levels of ketone bodies and somatic cell counts on days 30, 45 and 60 of the experiment, without changes in milk composition compared to the control group. Supplemented cows had lower levels reactive oxygen species and increased superoxide enzymes activity. Total protein, globulin and cytokine levels were higher in cows supplemented with mineral complexes. Therefore, we can conclude that subcutaneous mineral supplementation improved the immune response and minimized the oxidative stress in dairy cows during lactation.


Assuntos
Antioxidantes/metabolismo , Suplementos Nutricionais , Sistema Imunitário/efeitos dos fármacos , Leite/citologia , Minerais/farmacologia , Animais , Glicemia/análise , Bovinos , Contagem de Células/veterinária , Citocinas/sangue , Feminino , Injeções Subcutâneas/veterinária , Corpos Cetônicos/sangue , Leite/química , Período Pós-Parto , Espécies Reativas de Oxigênio/metabolismo , Soroalbumina Bovina/análise , Soroglobulinas/análise
18.
Am J Physiol Endocrinol Metab ; 315(5): E833-E847, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29944388

RESUMO

ß-Klotho (encoded by Klb) is an obligate coreceptor, mediating both fibroblast growth factor (FGF)15 and FGF21 signaling. Klb-/- mice are refractory to metabolic FGF15 and FGF21 action and exhibit derepressed (increased) bile acid (BA) synthesis. Here, we deeply phenotyped male Klb-/- mice on a pure C57BL/6J genetic background, fed a chow diet focusing on metabolic aspects. This aims to better understand the physiological consequences of concomitant FGF15 and FGF21 signaling deficiency, in particular on the gut-liver axis. Klb-/- mice present permanent growth restriction independent of adiposity and energy balance. Klb-/- mice also exhibit few changes in carbohydrate metabolism, combining normal gluco-tolerance, insulin sensitivity, and fasting response with increased gluconeogenic capacity and decreased glycogen mobilization. Livers of Klb-/- mice reveal pathologic features, including a proinflammatory status and initiation of fibrosis. These defects are associated to a massive shift in BA composition in the enterohepatic system and blood circulation featured by a large excess of microbiota-derived deoxycholic acid, classically known for its genotoxicity in the gastrointestinal tract. In conclusion, ß-Klotho is a gatekeeper of hepatic integrity through direct action (mediating FGF21 anti-inflammatory signaling) and indirect mechanisms (mediating FGF15 signaling that maintains BA level and composition).


Assuntos
Ácidos e Sais Biliares/metabolismo , Peso Corporal/fisiologia , Trato Gastrointestinal/metabolismo , Cirrose Hepática/metabolismo , Fígado/metabolismo , Proteínas de Membrana/metabolismo , Adiposidade/genética , Animais , Metabolismo Energético/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Gluconeogênese/fisiologia , Corpos Cetônicos/sangue , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Transdução de Sinais/fisiologia
19.
Clin Chem Lab Med ; 56(11): 1819-1827, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-29715177

RESUMO

Hypothermia is defined as a core body temperature below 35°C and can be caused by environmental exposure, drug intoxication, metabolic or nervous system dysfunction. This lethal pathology with medico-legal implications is complex to diagnose because macroscopic and microscopic lesions observed at the autopsy and the histological analysis are suggestive but not pathognomonic. Postmortem biochemical explorations have been progressively developed through the study of several biomarkers to improve the diagnosis decision cluster. Here, we present an updated review with novel biomarkers (such as catecholamines O-methylated metabolites, thrombomodulin and the cardiac oxyhemoglobin ratio) as well as some propositional interpretative postmortem thresholds and, to the best of our knowledge, for the first time, we present the most adapted strategy of sampling and analyses to identify biomarkers of hypothermia. For our consideration, the most relevant identified biomarkers are urinary catecholamines and their O-methylated metabolites, urinary free cortisol, blood cortisol, as well as blood, vitreous humor and pericardial fluid for ketone bodies and blood free fatty acids. These biomarkers are increased in response either to cold-mediated stress or to bioenergetics ketogenesis crisis and significantly contribute to the diagnosis by exclusion of death by hypothermia.


Assuntos
Biomarcadores/metabolismo , Hipotermia/diagnóstico , Biomarcadores/sangue , Catecolaminas/sangue , Catecolaminas/metabolismo , Ácidos Graxos não Esterificados/sangue , Ciências Forenses , Humanos , Hidrocortisona/sangue , Hipotermia/patologia , Corpos Cetônicos/sangue , Trombomodulina/sangue
20.
J Physiol Biochem ; 74(3): 417-429, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29752707

RESUMO

Cardiac arrest is one of the leading causes of death among adults in older age. Understanding mechanisms how organism responds to ischemia at global level is essential for the prevention and ischemic patient's treatment. In this study, we used a global cerebral ischemia induced by four-vessel occlusion as an established animal model for ischemic stroke to investigate metabolic changes after 24 h reperfusion, when transitions occur due to the onset of delayed neuronal death. We also focused on the endogenous phenomenon known as ischemic tolerance by the pre-ischemic treatment. The experiments were carried out on blood plasma samples as easily available and metabolically reflecting the overall changes in injured organism. Our results imply that disturbed glycolysis pathway, as a consequence of ischemic injury, leads to the increased level of ketone bodies (acetone, acetoacetate and ß-hydroxybutyrate) along with increased utilization of triacylglycerols in plasma of ischemic and ischemically preconditioned rats. Complementary to, a decreased level of glycolytic intermediates (lactate, pyruvate, acetate) with increased level of glucose was found in ischemic and preconditioned animals. The protective effect of ischemic preconditioning on metabolome recovery was demonstrated by significantly increased level of creatine compared to ischemic, non-preconditioned rats. We also document that acetoacetate, pyruvate, lactate, and leucine have the best discriminatory power between ischemic and control plasma. Conclusively, our results provide evidence that NMR spectra analysis can identify specific group of metabolites present in plasma with the capability for discrimination between individual groups of animals. In addition, an excellent feasibility for the statistical discrimination among ischemic, preconditioned, and control rats can be applied regardless of native or deproteinated plasma and also regardless of noesy or cpmg NMR acquisition.


Assuntos
Isquemia Encefálica/sangue , Transtornos Cerebrovasculares/sangue , Precondicionamento Isquêmico/métodos , Corpos Cetônicos/sangue , Metaboloma , Traumatismo por Reperfusão/sangue , Ácido Acético/sangue , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Isquemia Encefálica/patologia , Transtornos Cerebrovasculares/patologia , Creatina/sangue , Glicólise/fisiologia , Ácido Láctico/sangue , Espectroscopia de Ressonância Magnética , Masculino , Ácido Pirúvico/sangue , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologia , Triglicerídeos/sangue
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