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1.
Nutrients ; 13(3)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802709

RESUMO

Adherence is a critical factor to consider when interpreting study results from randomized clinical trials (RCTs) comparing one diet to another, but it is frequently not reported by researchers. The purpose of this secondary analysis of the Keto-Med randomized trial was to provide a detailed examination and comparison of the adherence to the two study diets (Well Formulated Ketogenic Diet (WFKD) and Mediterranean Plus (Med-Plus)) under the two conditions: all food being provided (delivered) and all food being obtained by individual participants (self-provided). Diet was assessed at six time points including baseline (×1), week 4 of each phase when participants were receiving food deliveries (×2), week 12 of each phase when participants were preparing and providing food on their own (×2), and 12 weeks after participants completed both diet phases and were free to choose their own diet pattern (×1). The adherence scores for WFKD and Med-Plus were developed specifically for this study. Average adherence to the two diet patterns was very similar during both on-study time points of the intervention. Throughout the study, a wide range of adherence was observed among participants-for both diet types and during both the delivery phase and self-provided phase. Insight from this assessment of adherence may aid other researchers when answering the important question of how to improve behavioral adherence during dietary trials. This study is registered at clinicaltrials.gov NCT03810378.


Assuntos
Dieta Cetogênica , Dieta Mediterrânea , Cooperação do Paciente , Estudos Cross-Over , Diabetes Mellitus Tipo 2/dietoterapia , Dieta Cetogênica/métodos , Dieta Cetogênica/psicologia , Dieta Mediterrânea/psicologia , Feminino , Abastecimento de Alimentos , Humanos , Corpos Cetônicos/sangue , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente/psicologia , Satisfação do Paciente , Estado Pré-Diabético/dietoterapia
2.
Nutrients ; 12(12)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33322022

RESUMO

Multiple sclerosis (MS) is a neurodegenerative disease that causes anthropometric changes characterised by functional disability, increase in fat mass, and decrease in lean mass. All these variables are related to a greater cardiac risk. The polyphenol epigallocatechin gallate (EGCG) and an increase in ketone bodies in the blood have been shown to have beneficial effects on anthropometric and biochemical variables related to cardiovascular activity. The aim of this study was to analyse the impact of the intervention with EGCG and ketone bodies on cardiac risk in MS patients. A population of 51 MS patients were randomly assigned to a control group and an intervention group (daily dose of 800 mg of EGCG and 60 mL of coconut oil). Both groups followed an isocaloric diet for 4 months. Levels of beta-hydroxybutyrate (BHB), albumin, paraoxonase 1 (PON1) and C-reactive protein (CRP) were measured in serum before and after the intervention, as well as determining functional ability, waist circumference, waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), fat percentage and muscle percentage. After 4 months, in the intervention group there was a significant increase in BHB, PON1 and albumin, while CRP did not vary; a significant decrease in cardiac risk associated with a significant decline in WHR; as well as a significant increase in muscle percentage. By contrast, these changes were not observed in the control group. Finally, results from analysis of variance (ANOVA) revealed a significant time-condition interaction effect, observing that WHtR and fat mass decreased in the intervention group, while they increased in the control group.


Assuntos
Cardiotônicos/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Catequina/análogos & derivados , Suplementos Nutricionais , Corpos Cetônicos/sangue , Esclerose Múltipla/terapia , Ácido 3-Hidroxibutírico/sangue , Adulto , Análise de Variância , Antropometria , Arildialquilfosfatase/sangue , Índice de Massa Corporal , Proteína C-Reativa/análise , Doenças Cardiovasculares/etiologia , Catequina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/complicações , Projetos Piloto , Albumina Sérica/análise , Resultado do Tratamento , Razão Cintura-Estatura
4.
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
5.
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
6.
BMC Vet Res ; 16(1): 41, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013972

RESUMO

BACKGROUND: Ketosis is a metabolic disorder often triggered by anorexia in animals fed on high energy diets. Although mostly described in pregnant female guinea pigs, under the name of pregnancy toxicosis; there is limited information on ketosis in males and non-pregnant females, often presented to clinics with anorexia or inappetence. The objective of this study was to observe progression of ketosis in guinea pigs, document the changes and evaluate diagnostic methods and a therapeutic approach. RESULTS: Twenty eight adult guinea pigs (Cavia porcellus), castrated males and intact females of obese and slim body condition were fasted for 3 days and refed afterwards. The slim animals served as control group for body condition. Either slim and fat animals were divided into two treatment groups: half of them received fluid replacements with glucose subcutaneously, the other half did not receive any injection and served as treatment control. Serum beta-hydroxybutyrate, and urine acetoacetate and acetone were measured during and after fasting. Serum ALT, bile acids and liver histology were also analyzed after 7 days of refeeding (and therapy). Females and obese guinea pigs showed a significantly higher increase in ketone bodies in serum and urine. Obese, female, or animals not receiving therapy needed more time to regulate ketone bodies to normal levels than slim animals, males or animals receiving therapy. Liver histology revealed increased hepatocyte degeneration and higher glycogen content in obese animals and animals receiving therapy, and additionally more glycogen content in males. Only minor hepatic fat accumulation was documented. Bile acids showed good correlation to histological liver changes whereas ALT did not. CONCLUSIONS: Female and obese animals react more intensively to fasting. As preventive management, animals should be kept in adequate body condition, fasting should be avoided, and anorexia should be treated immediately. In such a case, urinary dip sticks to detect ketone bodies are a useful diagnostic tool. Glucose therapy leads to faster cessation of ketogenesis and should be recommended in cases of ketosis. However, it needs to be adjusted to avoid hepatocyte glycogen overload and degeneration. Measuring bile acids presents a valuable indicator of liver damage.


Assuntos
Privação de Alimentos , Cetose/veterinária , Doenças dos Roedores/diagnóstico , Ácido 3-Hidroxibutírico/sangue , Acetoacetatos/urina , Acetona/urina , Fenômenos Fisiológicos da Nutrição Animal , Animais , Ácidos e Sais Biliares , Feminino , Glucose/administração & dosagem , Cobaias , Corpos Cetônicos/sangue , Corpos Cetônicos/urina , Cetose/diagnóstico , Cetose/terapia , Fígado/metabolismo , Fígado/patologia , Masculino , Obesidade/complicações , Obesidade/veterinária , Doenças dos Roedores/terapia
7.
J Cereb Blood Flow Metab ; 40(1): 177-186, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30353770

RESUMO

Adaptive metabolic response to injury includes the utilization of alternative energy substrates - such as ketone bodies (KB) - to protect the brain against further damage. Here, we examined cerebral ketone metabolism in patients with traumatic brain injury (TBI; n = 34 subjects) monitored with cerebral microdialysis to measure total brain interstitial tissue KB levels (acetoacetate and ß-hydroxybutyrate). Nutrition - from fasting vs. stable nutrition state - was associated with a significant decrease of brain KB (34.7 [10th-90th percentiles 10.7-189] µmol/L vs. 13.1 [6.5-64.3] µmol/L, p < 0.001) and blood KB (668 [168.4-3824.9] vs. 129.4 [82.6-1033.8] µmol/L, p < 0.01). Blood KB correlated with brain KB (Spearman's rho 0.56, p = 0.0013). Continuous feeding with medium-chain triglycerides-enriched enteral nutrition did not increase blood KB, and provided a modest increase in blood and brain free medium chain fatty acids. Higher brain KB at the acute TBI phase correlated with age and brain lactate, pyruvate and glutamate, but not brain glucose. These novel findings suggest that nutritional ketosis was the main determinant of cerebral KB metabolism following TBI. Age and cerebral metabolic distress contributed to brain KB supporting the hypothesis that ketones might act as alternative energy substrates to glucose. Further studies testing KB supplementation after TBI are warranted.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Corpos Cetônicos/metabolismo , Adulto , Fatores Etários , Encéfalo/metabolismo , Metabolismo Energético , Feminino , Humanos , Corpos Cetônicos/sangue , Cetonas/metabolismo , Masculino , Microdiálise , Pessoa de Meia-Idade
9.
Adv Ther ; 36(10): 2769-2782, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31444706

RESUMO

INTRODUCTION: We report a randomized, double-blind, placebo-controlled, 4-week study to investigate the effect of empagliflozin on free fatty acids and blood ketone bodies in Japanese patients with type 2 diabetes mellitus. METHODS: Patients (baseline mean [standard deviation] glycated hemoglobin 7.91% [0.80%]; body mass index 24.3 [3.2] kg/m2) were randomized to empagliflozin 10 mg (n = 20), empagliflozin 25 mg (n = 19), or placebo (n = 21) daily as monotherapy for 28 days. Meal tolerance tests (MTTs; breakfast, lunch, dinner) were performed on day - 1, day 1 (first day of treatment), and day 28. On day 1 and day 28, study drug was administered 1 h before breakfast. Free fatty acids and blood ketone bodies were measured before and 1, 2, and 3 h after each MTT, and the next morning (overnight fast). RESULTS: Empagliflozin significantly reduced plasma glucose and insulin and reduced body weight vs. placebo. Empagliflozin increased free fatty acids and total ketones bodies at day 1 and day 28. At day 28, the adjusted mean (95% confidence interval) difference vs. placebo in the time-corrected area under curve over 24 h for total ketone bodies was 67.1 (12.3, 121.8) µmol·h/L·h (P = 0.017) with empagliflozin 10 mg and 178.1 (123.9, 232.2) µmol·h/L·h (P < 0.001) with empagliflozin 25 mg. Increases in ketones with empagliflozin vs. placebo peaked just before and declined after meals, with the highest peak before breakfast. Changes in total ketone bodies appeared to be associated with changes in plasma glucose, insulin, and free fatty acids. CONCLUSION: Empagliflozin modestly increased free fatty acids and blood ketone bodies after a single dose and 28 days' treatment. Increases in ketones appeared to be related to the duration of fasting and were most pronounced before breakfast. Increases in ketones appeared to be associated with changes in well-known metabolic determinants of ketone production. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01947855. FUNDING: Boehringer Ingelheim & Eli Lilly and Company.


Assuntos
Compostos Benzidrílicos/metabolismo , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Glucosídeos/metabolismo , Glucosídeos/uso terapêutico , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Idoso , Grupo com Ancestrais do Continente Asiático , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Japão , Corpos Cetônicos/sangue , Corpos Cetônicos/metabolismo , Masculino , Pessoa de Meia-Idade
10.
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
11.
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
12.
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
13.
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
14.
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
15.
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
16.
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
17.
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
18.
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


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
19.
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


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
20.
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
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