RESUMO
This study investigated if paraxanthine (PX) impacts energy expenditure, lipolysis and perceptual responses. In a randomized, double-blind, placebo-controlled, crossover fashion, 21 adults (13 M, 8 F; 26.0 ± 6.4 years, 174.9 ± 11.5 cm, 81.0 ± 15.7 kg body mass, 26.3 ± 3.4 kg/m2) consumed a placebo (PLA), 100 mg (PX100), 200 mg (PX200), and 300 mg of PX (PX300, enfinity®, Ingenious Ingredients, L.P. Lewisville, TX, USA). Venous blood was collected 0, 30, 60, 90, 120 and 180 min (min) after ingestion and analyzed for glycerol and free fatty acids. Resting hemodynamics, metabolic rate and perceptual indicators of hunger, appetite and anxiety were evaluated. Mixed factorial analysis of variance were used to evaluate changes time within and between groups. Heart rate decreased in PX100 compared to PLA 60 (p = .022) and 180 min (p = .001). Blood pressure did not change. Hunger ratings in PLA increased 30 (p = .05), 60 (p = .04), 90 (p = .02), and 180 min (p = .05) after ingestion when compared to PX200. PX200 increased energy expenditure (all p < .05) when compared to PLA. Rates of fat oxidation tended to increase 90 (p = .056) and 120 min (p = .066) in PX200 compared to PLA. Free fatty acids increased in PX300 compared to PLA (p = .002). Glycerol did not change. Ingestion of PX200 augmented energy expenditure and hunger ratings when compared to PLA without impacting hemodynamics or lipolysis.
Assuntos
Apetite , Estudos Cross-Over , Metabolismo Energético , Fome , Lipólise , Humanos , Lipólise/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Adulto , Feminino , Masculino , Método Duplo-Cego , Apetite/efeitos dos fármacos , Fome/efeitos dos fármacos , Adulto Jovem , Relação Dose-Resposta a Droga , Glicerol/sangue , Ácidos Graxos não Esterificados/sangue , Frequência Cardíaca/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Suplementos NutricionaisRESUMO
BACKGROUND: Due to the increase in global temperature, it is necessary to investigate solutions so that athletes competing in hot conditions can perform in optimal conditions avoiding loss of performance and health problems. Therefore, this study aims to evaluate the effect of pre-exercise glycerol supplementation during a rectangular test at ambient temperature mid (28.2ºC) on dehydration variables in international race walkers. METHODS: Eight international male race walkers (age: 28.0 years (4.4); weight: 65.6 kg (6.6); height: 180.0 cm (5.0); fat mass: 6.72% (0.66); muscle mass: 33.3 kg (3.3); VO2MAX: 66.5 ml · kg-1·min-1 (1.9)) completed this randomized crossover design clinical trial. Subjects underwent two interventions: they consumed placebo (n = 8) and glycerol (n = 8) acutely, before a rectangular test where dehydration, RPE, metabolic, kinematic, and thermographic variables were analyzed before, during and after the test. RESULTS: After the intervention, significant differences were found between groups in body mass in favor of the placebo (Placebo: -2.23 kg vs Glycerol: -2.48 kg; p = 0.033). For other variables, no significant differences were found. CONCLUSION: Therefore, pre-exercise glycerol supplementation was not able to improve any dehydration, metabolic, kinematic, or thermographic variables during a rectangular test at temperature mid in international race walkers. Possibly, a higher environmental temperature could have generated a higher metabolic and thermoregulatory stress, generating differences between groups like other previous scientific evidence.
Assuntos
Estudos Cross-Over , Desidratação , Suplementos Nutricionais , Glicerol , Caminhada , Humanos , Masculino , Glicerol/administração & dosagem , Glicerol/sangue , Adulto , Caminhada/fisiologia , Fenômenos Biomecânicos , Termografia , Fenômenos Fisiológicos da Nutrição Esportiva , Adulto Jovem , Consumo de Oxigênio/efeitos dos fármacos , Temperatura Alta , Desempenho Atlético/fisiologiaRESUMO
AIMS/HYPOTHESIS: As a result of early loss of the glucagon response, adrenaline is the primary counter-regulatory hormone in type 1 diabetes. Diminished adrenaline responses to hypoglycaemia due to counter-regulatory failure are common in type 1 diabetes, and are probably induced by exposure to recurrent hypoglycaemia, however, the metabolic effects of adrenaline have received less research attention, and also there is conflicting evidence regarding adrenaline sensitivity in type 1 diabetes. Thus, we aimed to investigate the metabolic response to adrenaline and explore whether it is modified by prior exposure to hypoglycaemia. METHODS: Eighteen participants with type 1 diabetes and nine healthy participants underwent a three-step ascending adrenaline infusion during a hyperinsulinaemic-euglycaemic clamp. Continuous glucose monitoring data obtained during the week before the study day were used to assess the extent of hypoglycaemia exposure. RESULTS: While glucose responses during the clamp were similar between people with type 1 diabetes and healthy participants, plasma concentrations of NEFAs and glycerol only increased in the group with type 1 diabetes (p<0.001). Metabolomics revealed an increase in the most common NEFAs (p<0.01). Other metabolic responses were generally similar between participants with type 1 diabetes and healthy participants. Exposure to hypoglycaemia was negatively associated with the NEFA response; however, this was not statistically significant. CONCLUSIONS/INTERPRETATION: In conclusion, individuals with type 1 diabetes respond with increased lipolysis to adrenaline compared with healthy participants by mobilising the abundant NEFAs in plasma, whereas other metabolic responses were similar. This may suggest that the metabolic sensitivity to adrenaline is altered in a pathway-specific manner in type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05095259.
Assuntos
Glicemia , Diabetes Mellitus Tipo 1 , Epinefrina , Técnica Clamp de Glucose , Hipoglicemia , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/sangue , Epinefrina/sangue , Epinefrina/administração & dosagem , Ácidos Graxos não Esterificados/sangue , Glucagon/sangue , Glicerol/sangue , Glicerol/administração & dosagem , Hipoglicemia/sangue , Insulina/administração & dosagem , Estudos de Casos e ControlesRESUMO
We evaluated changes in hyperhydration and beverage hydration index (BHI, a composite measure of fluid balance after consuming a test beverage relative to water) during resting, induced by the consumption of beverages containing glycerol and sodium supplemented with fast-absorbing sucrose or slow-absorbing isomaltulose. In a randomized crossover, single-blinded protocol (clinical trials registry: UMIN000042644), 14 young physically active adults (three women) consumed 1 L of beverage containing either 7% glycerol + 0.5% sodium (Gly + Na), Gly + Na plus 7% sucrose (Gly + Na + Suc), Gly + Na plus 7% isomaltulose (Gly + Na + Iso), or water (CON) over a 40 min period. We assessed the change in plasma volume (ΔPV), BHI (calculated from cumulative urine output following consumption of water relative to that of the beverage), and blood glucose and sodium for 180 min after initiating ingestion. Total urine volume was reduced in all beverages containing glycerol and sodium compared to CON (all P ≤ 0.002). The addition of isomaltulose increased BHI by â¼45% (3.43 ± 1.0 vs. 2.50 ± 0.7 for Gly + Na, P = 0.011) whereas sucrose did not (2.6 ± 0.6, P = 0.826). The PV expansion was earliest for Gly + Na (30 min), slower for Gly + Na + Suc (90 min), and slowest for Gly + Na + Iso (120 min) with a concomitant lag in the increase of blood glucose and sodium concentrations. Supplementation of beverages containing glycerol and sodium with isomaltulose but not sucrose enhances BHI from those of glycerol and sodium only under a resting state, likely due to the slow absorption of isomaltulose-derived monosaccharides (i.e., glucose and fructose).
Assuntos
Estudos Cross-Over , Glicerol , Isomaltose , Isomaltose/análogos & derivados , Humanos , Isomaltose/administração & dosagem , Masculino , Feminino , Método Simples-Cego , Adulto Jovem , Glicerol/sangue , Adulto , Sacarose/administração & dosagem , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Bebidas , Glicemia/metabolismo , Sódio/urina , Sódio/sangue , Volume PlasmáticoRESUMO
Wild-type (WT) mice maintain viable levels of blood glucose even when adipose stores are depleted by 6 d of 60% calorie restriction followed by a 23-h fast (hereafter designated as "starved" mice). Survival depends on ghrelin, an octanoylated peptide hormone. Mice that lack ghrelin suffer lethal hypoglycemia when subjected to the same starvation regimen. Ghrelin is known to stimulate secretion of growth hormone (GH), which in turn stimulates secretion of IGF-1 (insulin-like growth factor-1). In the current study, we found that starved ghrelin-deficient mice had a 90% reduction in plasma IGF-1 when compared with starved WT mice. Injection of IGF-1 in starved ghrelin-deficient mice caused a twofold increase in glucose production and raised blood glucose to levels seen in starved WT mice. Increased glucose production was accompanied by increases in plasma glycerol, fatty acids and ketone bodies, and hepatic triglycerides. All of these increases were abolished when the mice were treated with atglistatin, an inhibitor of adipose tissue triglyceride lipase. We conclude that IGF-1 stimulates adipose tissue lipolysis in starved mice and that this lipolysis supplies energy and substrates that restore hepatic gluconeogenesis. This action of IGF-1 in starved mice is in contrast to its known action in inhibiting adipose tissue lipase in fed mice. Surprisingly, the ghrelin-dependent maintenance of plasma IGF-1 in starved mice was not mediated by GH. Direct injection of GH into starved ghrelin-deficient mice failed to increase plasma IGF-1. These data call attention to an unsuspected role of IGF-1 in the adaptation to starvation.
Assuntos
Glicemia , Fator de Crescimento Insulin-Like I , Inanição , Adaptação Fisiológica , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/enzimologia , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Ácidos Graxos/sangue , Grelina/metabolismo , Gluconeogênese , Glicerol/sangue , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/metabolismo , Corpos Cetônicos/sangue , Lipase/antagonistas & inibidores , Lipase/metabolismo , Lipólise , Fígado/metabolismo , Camundongos , Compostos de Fenilureia/farmacologia , Inanição/sangue , Inanição/metabolismo , Triglicerídeos/metabolismoRESUMO
Male hypogonadism is a disorder characterized by low levels of testosterone, but patients can either show normal insulin (insulin-sensitive (IS)) or over time they can become insulin-resistant (IR). Since the two groups showed different altered metabolisms, testosterone replacement therapy (TRT) could achieve different results. In this paper, we analyzed plasma from 20 IS patients with low testosterone (<8 nmol/L) and HOMAi < 2.5. The samples, pre- and post-treatment with testosterone for 60 days, were analyzed by UHPLC and mass spectrometry. Glycolysis was significantly upregulated, suggesting an improved glucose utilization. Conversely, the pentose phosphate pathway was reduced, while the Krebs cycle was not used. Branched amino acids and carnosine metabolism were positively influenced, while ß-oxidation of fatty acids (FFA) was not activated. Cholesterol, HDL, and lipid metabolism did not show any improvements at 60 days but did so later in the experimental period. Finally, both malate and glycerol shuttle were reduced. As a result, both NADH and ATP were significantly lower. Interestingly, a significant production of lactate was observed, which induced the activation of the Cori cycle between the liver and muscles, which became the main source of energy for these patients without involving alanine. Thus, the treatment must be integrated with chemicals which are not restored in order to reactivate energy production.
Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Carnosina/sangue , Glicerol/sangue , Terapia de Reposição Hormonal/métodos , Hipogonadismo/tratamento farmacológico , Malatos/sangue , Metabolômica/métodos , Adulto , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Glicólise , Humanos , Hipogonadismo/sangue , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Via de Pentose FosfatoRESUMO
Vitamin D is necessary for musculoskeletal health, however, the supplementation of vitamin D above the sufficiency level does not bring additional bone mass density (BMD), unlike physical exercise which enhances the bone formatting process. Regular physical activity has been shown to upregulate VDR expression in muscles and to increase circulating vitamin D. Here we investigate whether a single bout of exercise might change 25(OH)D3 blood concentration and how it affects metabolic response to exercise. Twenty-six boys, 13.8 years old (SD ± 0.7) soccer players, participated in the study. The participants performed one of two types of exercise: the first group performed the VO2max test until exhaustion, and the second performed three times the repeated 30 s Wingate Anaerobic Test (WAnT). Blood was collected before, 15 min and one hour after the exercise. The concentration of 25(OH)D3, parathyroid hormone (PTH), interleukin-6 (IL-6), lactate, non-esterified fatty acids (NEFA) and glycerol were determined. 25(OH)D3 concentration significantly increased after the exercise in all boys. The most prominent changes in 25(OH)D3, observed after WAnT, were associated with the rise of PTH. The dimensions of response to the exercises observed through the changes in the concentration of 25(OH)D3, PTH, NEFA and glycerol were associated with the significant increases of IL-6 level. A single bout of exercise may increase the serum's 25(OH)D3 concentration in young trained boys. The intensive interval exercise brings a more potent stimulus to vitamin D fluctuations in young organisms. Our results support the hypothesis that muscles may both store and release 25(OH)D3.
Assuntos
Calcifediol/sangue , Exercício Físico/fisiologia , Músculo Esquelético/fisiologia , Hormônio Paratireóideo/sangue , Aptidão Física/fisiologia , Adolescente , Atletas , Ácidos Graxos não Esterificados/sangue , Glicerol/sangue , Humanos , Interleucina-6/sangue , Ácido Láctico/sangue , Masculino , Projetos Piloto , Testes de Função RespiratóriaRESUMO
When plasma triglyceride is assessed in standard laboratories, it is a measurement of plasma glycerol after hydrolysis of triglycerides into fatty acids and glycerol. In most patients, the plasma level of free glycerol will only marginally influence the measurement of plasma triglyceride. However, in rare cases elevated free glycerol concentrations causes pseudohypertriglyceridemia and blanking for free glycerol becomes important. In this study, we investigated the plasma free glycerol level in 100 adult men with mild to moderate hypertriglyceridemia to assess the need for providing a free glycerol measurement in our clinical biochemistry department. The plasma samples were obtained in our blood sampling facility that receives both in- and outpatients. The highest plasma level of free glycerol observed was 300 µmol/L and in 99% of the investigated men the inclusion of plasma free glycerol in the measurement of plasma triglyceride cause a less than 10% false increase in plasma triglyceride. A weak positive correlation between the plasma levels of free glycerol and triglyceride was observed. When subdividing the cohort into mild and moderate hypertriglyceridemia, the positive correlation was only maintained in the moderate hypertriglyceridemia group that also demonstrated a 23% higher plasma glycerol level than men with mild hypertriglyceridemia. We conclude that even though glycerol blanking is relevant in rare occasions, then this study does not support providing such a measurement in our department. The positive correlation between free glycerol and triglyceride in this cohort likely reflects a shared association with metabolic dysregulation.
Assuntos
Glicerol/sangue , Hipertrigliceridemia/sangue , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
BACKGROUND: It is commonly accepted that in obesity free fatty acids (FFA) cause insulin resistance and hyperglycemia, which drives hyperinsulinemia. However, hyperinsulinemia is observed in subjects with normoglycaemia and thus the paradigm above should be reevaluated. METHODS: We describe two studies: MD-Lipolysis, a case control study investigating the mechanisms of obesity-driven insulin resistance by a systemic metabolic analysis, measurements of adipose tissue lipolysis by microdialysis, and adipose tissue genomics; and POEM, a cohort study used for validating differences in circulating metabolites in relation to adiposity and insulin resistance observed in the MD-Lipolysis study. FINDINGS: In insulin-resistant obese with normal glycaemia from the MD-Lipolysis study, hyperinsulinemia was associated with elevated FFA. Lipolysis, assessed by glycerol release per adipose tissue mass or adipocyte surface, was similar between obese and lean individuals. Adipose tissue from obese subjects showed reduced expression of genes mediating catecholamine-driven lipolysis, lipid storage, and increased expression of genes driving hyperplastic growth. In the POEM study, FFA levels were specifically elevated in obese-overweight subjects with normal fasting glucose and high fasting levels of insulin and C-peptide. INTERPRETATION: In obese subjects with normal glycaemia elevated circulating levels of FFA at fasting are the major metabolic derangement candidate driving fasting hyperinsulinemia. Elevated FFA in obese with normal glycaemia were better explained by increased fat mass rather than by adipose tissue insulin resistance. These results support the idea that hyperinsulinemia and insulin resistance may develop as part of a homeostatic adaptive response to increased adiposity and FFA. FUNDING: Swedish-Research-Council (2016-02660); Diabetesfonden (DIA2017-250; DIA2018-384; DIA2020-564); Novo-Nordisk-Foundation (NNF17OC0027458; NNF19OC0057174); Cancerfonden (CAN2017/472; 200840PjF); Swedish-ALF-agreement (2018-74560).
Assuntos
Ácidos Graxos não Esterificados/metabolismo , Hiperinsulinismo/patologia , Obesidade/patologia , Tecido Adiposo/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Ácidos Graxos não Esterificados/sangue , Feminino , Regulação da Expressão Gênica , Glicerol/sangue , Glicerol/metabolismo , Humanos , Hiperinsulinismo/complicações , Insulina/sangue , Resistência à Insulina , Lipólise , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Análise de Componente PrincipalRESUMO
BACKGROUND: Decaffeinated green tea extract (dGTE) can increase fat oxidation during leg exercise, but dGTE is unsuitable for many people (e.g., those with injuries/disabilities), and its effects on arm exercise and women are unknown. METHODS: Eight adults (23-37 years old, 4 women) performed an incremental arm cycle test to measure peak oxygen uptake (VO2peak), followed by four 1-h trials at 50% VO2peak. Subjects were randomly assigned to 650 mg of dGTE or placebo (PLA) for 4 weeks followed by a 4-week washout and crossover trial. Blood samples were obtained pre-exercise and post-exercise for glycerol and free fatty acid analysis. Respiratory gases were collected continuously. RESULTS: VO2 showed no differences across trials ((0.83-0.89) ± (0.19-0.25) L/min, pâ¯=â¯0.460), neither did energy expenditure ((264-266) ± (59-77) kcal, pâ¯=â¯0.420) nor fat oxidation (dGTEâ¯=â¯0.11 to 0.12 g/min vs. PLAâ¯=â¯0.10 to 0.09 g/min, pâ¯=â¯0.220). Fat oxidation as percentage of energy expenditure was not different for dGTE vs. PLA (23% ± 12% to 25% ± 11% vs. 23% ± 10% to 21% ± 9%, pâ¯=â¯0.532). Glycerol concentration increased post-exercise in all trials, independent of treatments (preâ¯=â¯(3.4-5.1) ± (0.6-2.6) mg/dL vs. postâ¯=â¯(7.9-9.8) ± (2.6-3.7) mg/dL, pâ¯=â¯0.867, η2â¯=â¯0.005 for interaction), as did free fatty acid ((3.5-4.8) ± (1.4-2.2) mg/dL vs. (7.2-9.1) ± (2.6-4.5) mg/dL, pâ¯=â¯0.981, η2â¯=â¯0.000). CONCLUSION: Chronic dGTE supplementation had no effect on lipolysis and fat oxidation during arm cycle exercise in men and women.
Assuntos
Camellia sinensis/química , Exercício Físico , Lipólise/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Extratos Vegetais/farmacologia , Chá/química , Adulto , Braço , Estudos Cross-Over , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos não Esterificados/sangue , Feminino , Glicerol/sangue , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Placebos , Extratos Vegetais/administração & dosagem , Fatores de Tempo , Adulto JovemRESUMO
This study investigated the effect of decaffeinated green tea extract (dGTE), with or without antioxidant nutrients, on fat oxidation, body composition and cardio-metabolic health measures in overweight individuals engaged in regular exercise. Twenty-seven participants (20 females, 7 males; body mass: 77.5 ± 10.5 kg; body mass index: 27.4 ± 3.0 kg·m2; peak oxygen uptake (O2peak): 30.2 ± 5.8 mL·kg-1·min-1) were randomly assigned, in a double-blinded manner, either: dGTE (400 mg·d-1 (-)-epigallocatechin-3-gallate (EGCG), n = 9); a novel dGTE+ (400 mg·d-1 EGCG, quercetin (50 mg·d-1) and α-lipoic acid (LA, 150 mg·d-1), n = 9); or placebo (PL, n = 9) for 8 weeks, whilst maintaining standardised, aerobic exercise. Fat oxidation ('FATMAX' and steady state exercise protocols), body composition, cardio-metabolic and blood measures (serum glucose, insulin, leptin, adiponectin, glycerol, free fatty acids, total cholesterol, high [HDL-c] and low-density lipoprotein cholesterol [LDL-c], triglycerides, liver enzymes and bilirubin) were assessed at baseline, week 4 and 8. Following 8 weeks of dGTE+, maximal fat oxidation (MFO) significantly improved from 154.4 ± 20.6 to 224.6 ± 23.2 mg·min-1 (p = 0.009), along with a 22.5% increase in the exercise intensity at which fat oxidation was deemed negligible (FATMIN; 67.6 ± 3.6%O2peak, p = 0.003). Steady state exercise substrate utilisation also improved for dGTE+ only, with respiratory exchange ratio reducing from 0.94 ± 0.01 at week 4, to 0.89 ± 0.01 at week 8 (p = 0.004). This corresponded with a significant increase in the contribution of fat to energy expenditure for dGTE+ from 21.0 ± 4.1% at week 4, to 34.6 ± 4.7% at week 8 (p = 0.006). LDL-c was also lower (normalised fold change of -0.09 ± 0.06) for dGTE+ by week 8 (p = 0.038). No other significant effects were found in any group. Eight weeks of dGTE+ improved MFO and substrate utilisation during exercise, and lowered LDL-c. However, body composition and cardio-metabolic markers in healthy, overweight individuals who maintained regular physical activity were largely unaffected by dGTE.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Antioxidantes/administração & dosagem , Sobrepeso/terapia , Extratos Vegetais/administração & dosagem , Chá , Adiponectina/sangue , Adulto , Bilirrubina/sangue , Glicemia/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Índice de Massa Corporal , Fatores de Risco Cardiometabólico , Colesterol/sangue , Método Duplo-Cego , Metabolismo Energético/efeitos dos fármacos , Enzimas/sangue , Exercício Físico/fisiologia , Ácidos Graxos não Esterificados/sangue , Feminino , Glicerol/sangue , Humanos , Insulina/sangue , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Sobrepeso/fisiopatologia , Oxirredução/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacosRESUMO
Preeclampsia remains a leading cause of maternal and perinatal morbidity and mortality. Accurate prediction of preeclampsia risk would enable more effective, risk-based prenatal care pathways. Current risk assessment algorithms depend on clinical risk factors largely unavailable for first-time pregnant women. Delivering accurate preeclampsia risk assessment to this cohort of women, therefore requires for novel biomarkers. Here, we evaluated the relevance of metabolite biomarker candidates for their selection into a prototype rapid, quantitative Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS) based clinical screening assay. First, a library of targeted LC-MS/MS assays for metabolite biomarker candidates was developed, using a medium-throughput translational metabolomics workflow, to verify biomarker potential in the Screening-for-Pregnancy-Endpoints (SCOPE, European branch) study. A variable pre-selection step was followed by the development of multivariable prediction models for pre-defined clinical use cases, i.e., prediction of preterm preeclampsia risk and of any preeclampsia risk. Within a large set of metabolite biomarker candidates, we confirmed the potential of dilinoleoyl-glycerol and heptadecanoyl-2-hydroxy-sn-glycero-3-phosphocholine to effectively complement Placental Growth Factor, an established preeclampsia biomarker, for the prediction of preeclampsia risk in first-time pregnancies without overt risk factors. These metabolites will be considered for integration in a prototype rapid, quantitative LC-MS/MS assay, and subsequent validation in an independent cohort.
Assuntos
Biomarcadores/sangue , Metabolômica/métodos , Fator de Crescimento Placentário/sangue , Pré-Eclâmpsia/diagnóstico , Adulto , Austrália , Estudos de Casos e Controles , Cromatografia Líquida , Diagnóstico Precoce , Feminino , Glicerol/sangue , Humanos , Idade Materna , Análise Multivariada , Nova Zelândia , Pré-Eclâmpsia/sangue , Gravidez , Segundo Trimestre da Gravidez/sangue , Espectrometria de Massas em TandemRESUMO
Tissues may respond differently to a particular stimulus if they have been previously exposed to that same stimulus. Here, we tested the hypothesis that a strong metabolic stimulus such as fasting may influence the hepatic response to a subsequent fast and thus elicit a memory effect. Overnight fasting in mice significantly increased plasma free fatty acids, glycerol, ß-hydroxybutyrate, and liver triglycerides, and decreased plasma glucose, plasma triglycerides, and liver glycogen levels. In addition, fasting dramatically changed the liver transcriptome, upregulating genes involved in gluconeogenesis and in uptake, oxidation, storage, and mobilization of fatty acids, and downregulating genes involved in fatty acid synthesis, fatty acid elongation/desaturation, and cholesterol synthesis. Fasting also markedly impacted the liver metabolome, causing a decrease in the levels of numerous amino acids, glycolytic-intermediates, TCA cycle intermediates, and nucleotides. However, these fasting-induced changes were unaffected by two previous overnight fasts. Also, no significant effect was observed of prior fasting on glucose tolerance. Finally, analysis of the effect of fasting on the transcriptome in hepatocyte humanized mouse livers indicated modest similarity in gene regulation in mouse and human liver cells. In general, genes involved in metabolic pathways were upregulated or downregulated to a lesser extent in human liver cells than in mouse liver cells. In conclusion, we found that previous exposure to fasting in mice did not influence the hepatic response to a subsequent fast, arguing against the concept of metabolic memory in the liver. Our data provide a useful resource for the study of liver metabolism during fasting.
Assuntos
Jejum/sangue , Hepatócitos/metabolismo , Fígado/metabolismo , Metaboloma , Transcriptoma , Ácido 3-Hidroxibutírico/sangue , Animais , Glicemia/análise , Células Cultivadas , Ácidos Graxos não Esterificados/sangue , Gluconeogênese/genética , Teste de Tolerância a Glucose , Glicerol/sangue , Glicogênio/metabolismo , Humanos , Masculino , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Endogâmicos C57BL , Triglicerídeos/sangueRESUMO
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) effectively lower plasma glucose (PG) concentration in patients with type 2 diabetes, but studies have suggested that circulating glucagon concentrations and endogenous glucose production (EGP) are increased by SGLT2i, possibly compromising their glucose-lowering ability. To tease out whether and how glucagon may influence the glucose-lowering effect of SGLT2 inhibition, we subjected 12 patients with type 2 diabetes to a randomized, placebo-controlled, double-blinded, crossover, double-dummy study comprising, on 4 separate days, a liquid mixed-meal test preceded by single-dose administration of either 1) placebo, 2) the SGLT2i empagliflozin (25 mg), 3) the glucagon receptor antagonist LY2409021 (300 mg), or 4) the combination empagliflozin + LY2409021. Empagliflozin and LY2409021 individually lowered fasting PG compared with placebo, and the combination further decreased fasting PG. Previous findings of increased glucagon concentrations and EGP during acute administration of SGLT2i were not replicated in this study. Empagliflozin reduced postprandial PG through increased urinary glucose excretion. LY2409021 reduced EGP significantly but gave rise to a paradoxical increase in postprandial PG excursion, which was annulled by empagliflozin during their combination (empagliflozin + LY2409021). In conclusion, our findings do not support that an SGLT2i-induced glucagonotropic effect is of importance for the glucose-lowering property of SGLT2 inhibition.
Assuntos
Compostos Benzidrílicos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Diabetes Mellitus Tipo 2/terapia , Glucagon/metabolismo , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/sangue , Compostos Benzidrílicos/farmacocinética , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/sangue , Compostos de Bifenilo/farmacocinética , Glicemia/efeitos dos fármacos , Peptídeo C/metabolismo , Quimioterapia Combinada , Metabolismo Energético/efeitos dos fármacos , Esvaziamento Gástrico/efeitos dos fármacos , Glucosídeos/administração & dosagem , Glucosídeos/sangue , Glucosídeos/farmacocinética , Glicerol/sangue , Glicerol/metabolismo , Meia-Vida , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/sangue , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinéticaRESUMO
Pregnancy toxemia is the most frequent metabolic disorder of ewes in late pregnancy. Although propylene glycol (PG) and glycerol (GLY) are common glucogenic supplements for treating pregnancy toxemia in ewes, the relative benefit of these 2 supplements is not entirely clear. Therefore, the objectives of the present study were to determine the changes during 24 h in key blood metabolites and insulin in response to PG or GLY drenching in prolific ewes. To this end, 36 multiparous late-pregnant Afec-Assaf ewes (â¼132.4 d pregnant) bearing 2 to 4 fetuses, divided into 2 blocks (18 ewes in each block), with a blood ß-hydroxybutyrate (BHB) concentration of 0.5 to 1.6 mmol/L were included. Ewes were divided into 3 groups (12 ewes each; 6 ewes in each experimental day), according to their BHB levels, expected litter size, body weight, and body condition score, and were drenched with the following: (1) control group (CTL), 55 mL of water; (2) PG, 106 mL of PG (100% PG, 448 calories); or (3) GLY, 108 mL of Koforin 80 (80% GL; 448 calories). Blood samples were taken before drenching and every hour after drenching for 24 h. Plasma concentration of glucose, BHB, nonesterified fatty acids, lactate, glycerol, and insulin were determined. Because there were no effects of treatments after 12 h in the first block, the data were analyzed for 12 h after drenching rather than 24 h. The plasma glucose concentration during the first 5 h after drenching was the highest in the GLY, BHB concentration was the lowest in the PG, and the nonesterified fatty acid levels were lower in the PG compared with the CTL ewes during the first 5 h after drenching. However, glucose concentration was higher in the PG ewes at 9, 11, and 12 h after drenching than in CTL or GLY ewes. The mean lactate concentration in plasma for 12 h was 2.5- and 1.9-fold higher in the PG compared with the CTL and GLY ewes, respectively, and except at 11 h after drenching, it was significantly higher at each time point. The insulin concentration was higher in the GLY than in both other groups at 2 to 5 h after drenching. These results suggest that during the first few hours after drenching the effect of PG was more effective in reducing the BHB concentration, whereas the GLY effect was more effective in enhancing glucose concentration. The increased concentration in lactate following PG treatment suggests that the PG contribution to gluconeogenesis is mediated through its metabolism to lactate. In contrast, the lack of an effect on lactate, and the faster increase in blood glucose in response to GLY suggest that GLY has a more advanced entry point to gluconeogenesis, which influences the immediate response in enhancing the glucose blood concentration.
Assuntos
Ácido 3-Hidroxibutírico/sangue , Glicemia/análise , Glicerol/administração & dosagem , Propilenoglicol/administração & dosagem , Ovinos/sangue , Animais , Suplementos Nutricionais , Ácidos Graxos não Esterificados/sangue , Feminino , Idade Gestacional , Gluconeogênese/efeitos dos fármacos , Glicerol/sangue , Insulina/sangue , Lactação/efeitos dos fármacos , Ácido Láctico/sangue , Pré-Eclâmpsia/prevenção & controle , Pré-Eclâmpsia/veterinária , Gravidez , Doenças dos Ovinos/prevenção & controleRESUMO
SCOPE: Inadequate intake of choline commonly leads to liver diseases. Methionine- and choline-deficient diets (MCDD) induce fatty liver in mice which is partly mediated by triglyceride (TG) lipolysis in white adipose tissues (WATs). Because Fatp4 knockdown has been shown to increase adipocyte lipolysis in vitro, here, the effects of MCDD on WAT lipolysis in aP2-Cre Fatp4-knockout (Fatp4A-/- ) mice are determined. METHODS AND RESULTS: Isolated WATs of Fatp4A-/- mice exposed to MCD medium show an increase in lipolysis, and the strongest effect is noted on glycerol release from subcutaneous fat. Fatp4A-/- mice fed with MCDD for 4 weeks show an increase in serum glycerol, TG, and leptin levels associated with the activation of hormone-sensitive lipase in subcutaneous fat. Chow-fed Fatp4A-/- mice also show an increase in serum leptin and very-low-density lipoproteins as well as liver phosphatidylcholine and sphingomyelin levels. Both chow- and MCDD-fed Fatp4A-/- mice show a decrease in serum ketone and WAT sphingomyelin levels which supports a metabolic shift to TG for subsequent WAT lipolysis CONCLUSIONS: Adipose Fatp4 deficiency leads to TG lipolysis and leptin release, which are exaggerated by MCDD. The data imply hyperlipidemia risk by a low dietary choline intake and gene mutations that increase adipose TG levels.
Assuntos
Tecido Adiposo/metabolismo , Colina/farmacologia , Leptina/metabolismo , Lipólise/fisiologia , Metionina/farmacologia , Tecido Adiposo/efeitos dos fármacos , Animais , Dieta , Proteínas de Transporte de Ácido Graxo/genética , Feminino , Glicerol/sangue , Cetonas/sangue , Leptina/sangue , Lipólise/efeitos dos fármacos , Fígado/patologia , Masculino , Metionina/deficiência , Camundongos Knockout , Camundongos Transgênicos , Triglicerídeos/sangueRESUMO
BACKGROUND: Triglyceride (TG) is a tri-ester composed of a glycerol and 3 fatty acids. Degradation of TG in adipose tissue is increased in the fasting state but inhibited in the postprandial state. Although insulin suppresses adipose TG degradation, patients with insulin resistance have high concentrations of insulin and free glycerol (FG) in the fasting state. OBJECTIVE: We examined whether the fasting FG concentration reflects visceral obesity and insulin sensitivity in middle-aged Japanese men. METHODS: We measured the fasting serum FG concentration in 72 males aged 30 to 50 years using a simple enzymatic method. The subjects were divided into tertiles according to their homeostasis model assessment of insulin resistance (HOMA-IR). Besides routine glucose- and lipid-related parameters, we determined insulin sensitivity as the rate of glucose disappearance in a 2-step hyperinsulinemic-euglycemic clamp and the abdominal visceral fat area (VFA) by magnetic resonance imaging. RESULTS: The highest HOMA-IR tertile group had a higher fasting FG concentration than the middle- and lowest-tertile groups (0.077 ± 0.024 vs 0.063 ± 0.017 and 0.061 ± 0.016 mmol/L, P < .05 and P < .01). The FG concentration was positively correlated with VFA (rs = 0.36; P < .01) and the HOMA-IR score (rs = 0.26, P < .05) but negatively correlated with insulin sensitivity (rs = -0.26, P < .05). Multivariate regression analysis revealed that the FG concentration is independently associated with VFA and insulin sensitivity. CONCLUSION: The fasting FG concentration reflects VFA and insulin sensitivity in middle-aged Japanese men. The fasting FG concentration may be a potential surrogate marker of visceral obesity and insulin resistance in outpatients.
Assuntos
Jejum/sangue , Glicerol/sangue , Resistência à Insulina , Obesidade Abdominal/sangue , Tecido Adiposo/patologia , Adulto , Idoso , Biomarcadores/sangue , Glicemia/metabolismo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/metabolismo , Obesidade Abdominal/patologia , Período Pós-Prandial , Triglicerídeos/sangueRESUMO
Brown adipose tissue generates heat via the mitochondrial uncoupling protein UCP1 to protect against obesity and hypothermia. Fas mutant MRL/lpr mice exhibit a significantly leaner phenotype compared to wild type MRL/MpJ mice. In this study, we evaluated the inflammatory cell population in the adipose tissue of MRL/lpr mice, which could potentially influence their lean phenotype. Furthermore, we compared beige fat activity between the MRL/MpJ and MRL/lpr mice. Fas mutation resulted in high body temperature, improved glucose tolerance, and decreased fat mass and adipocyte size. Fas mutation prevented high-fat diet-induced obesity and decreased the white adipose tissue M1:M2 ratio. When mice were fed a high-fat diet, UCP1, IL-4, IL-10, and tyrosine hydroxylase genes had significantly higher expression in Fas-mutant mice than in wild type mice. After a cold challenge, UCP1 expression and browning were also significantly higher in the Fas-mutant mice. In summary, Fas-mutant mice are resistant to high-fat diet-induced obesity due to increased IL-4 and IL-10 levels and the promotion of thermogenic protein activity and browning in their adipose tissues. STAT6 activation might contribute to M2 polarisation by increasing IL-4 and IL-10 levels while increases in M2 and tyrosine hydroxylase levels promote browning in response to Fas mutation.
Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Mutação/genética , Obesidade/genética , Receptor fas/genética , Animais , Colesterol/sangue , Dieta Hiperlipídica , Metabolismo Energético , Epididimo/patologia , Teste de Tolerância a Glucose , Glicerol/sangue , Inflamação/genética , Inflamação/patologia , Insulina/sangue , Leptina/sangue , Masculino , Camundongos , Obesidade/sangue , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , TermogêneseRESUMO
SCOPE: Abdominal obesity is one of the main modifiable risk factors of age-related cardiometabolic disease. Cardiometabolic disease risk and its associated high abdominal fat mass, cholesterol, and glucose concentrations can be reduced by a healthier lifestyle. Hence, the aim is to understand the relation between lifestyle-induced changes in body composition, and specifically abdominal fat, and accompanying changes in circulating metabolic biomarkers. METHODS AND RESULTS: Data from the Growing Old Together (GOTO) study was used, which is a single arm lifestyle intervention in which 164 older adults (mean age 63 years, BMI 23-35 kg/m2 ) changed their lifestyle during 13 weeks by 12.5% caloric restriction plus 12.5% increase in energy expenditure. It is shown here that levels of circulating metabolic biomarkers, even after adjustment for body mass index, specifically associate with abdominal fat mass. The applied lifestyle intervention mainly reduces abdominal fat mass (-2.6%, SD = 3.0) and this reduction, when adjusted for general weight loss, is highly associated with decreased circulating glycerol concentrations and increased HDL diameter. CONCLUSION: The lifestyle-induced reduction of abdominal fat mass is particularly associated, independent of body mass index or general weight loss, with decreased circulating glycerol concentrations and increased HDL diameter.
Assuntos
Gordura Abdominal , Glicerol/sangue , Estilo de Vida , Obesidade/terapia , Idoso , Biomarcadores/sangue , Composição Corporal , Restrição Calórica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismoRESUMO
The ergogenic effect of caffeine is well established, although no investigations providing a high carbohydrate feeding strategy (pre-exercise meal=2 g/kg BM) co-ingested with caffeine exist for soccer. This investigation examines the effect of caffeine in addition to a pre-exercise carbohydrate meal and drink mid-way through a soccer simulation. Eight recreational soccer players completed an 85-minute soccer simulation followed by an exercise capacity test (Yo-yo Intermittent Endurance test level 2) on two occasions. Prior to exercise participants consumed a high carbohydrate meal, with placebo or 5 mg/kg BM-1 caffeine. No significant performance effect was identified (p=0.099) despite a 12.8% (109 m) improvement in exercise capacity following caffeine. Rates of carbohydrate and fat oxidation did not differ between conditions and nor were differences apparent for plasma glucose, fatty acids, glycerol, ß-hydroxybutyrate (p>0.05). However, an increase in lactate was observed for caffeine (p=0.039). A significant condition effect on rating of perceived exertion was identified (p<0.001), with the overall mean for the protocol lowered to 11.7±0.9 au for caffeine compared to 12.8±1.3 au. Caffeine supplementation with a carbohydrate feeding strategy failed to affect metabolic and metabolite responses, although reductions in perception of exercise were observed. While a 12.8% increase in exercise capacity was noted the findings were not significant, possibly due to the small sample size.