Plasma Acetate Research Articles

A phase I, open-label, single-dose, mass balance study of 14C-labeled abiraterone acetate in healthy male subjects

1. Metabolic disposition of 14C-abiraterone acetate (AA), a prodrug of abiraterone was assessed in a phase I, open-label, single-dose (1000 mg, approximately 100 μCi) study in healthy males (18–55 years, N = 8). Blood, urine, and faecal samples were obtained at specified timepoints for determination of abiraterone concentrations in the plasma, total radioactivity (TR), and the metabolite profile.2. Most plasma AA concentrations were below the limit of quantification. The mean maximum plasma concentration (Cmax) of abiraterone was 10.4 ng/mL, mean area under the plasma concentration-time curve (AUC) from 0 to the last measurable plasma concentration (AUC0–last) was 74.8 ng·h/mL. The exposures for TR in plasma (Cmax = 3429 ng·eq/mL; AUC0–last = 26,683 ng eq·h/mL) and whole blood (Cmax = 1836 ng·eq/mL; AUC0–last = 12,162 ng·eq·h/mL) were >300-fold higher than abiraterone exposure in plasma. The majority of TR resided in the plasma compartment of blood.3. Main circulating metabolites were abiraterone sulfate and N-oxide abiraterone sulfate. The main metabolite excreted in urine was N-oxide abiraterone sulfate (4.22% of TR). Major components of TR in faeces were unchanged AA (55.3% of TR) and abiraterone (22.3% of TR). Mean recovery of TR in faeces was 87.9%, indicating faeces as primary route of excretion.

Acute alcohol intoxication decreases glucose metabolism but increases acetate uptake in the human brain

Alcohol intoxication results in marked reductions in brain glucose metabolism, which we hypothesized reflect not just its GABAergic enhancing effects but also the metabolism of acetate as an alternative brain energy source. To test this hypothesis we separately assessed the effects of alcohol intoxication on brain glucose and acetate metabolism using Positron Emission Tomography (PET). We found that alcohol intoxication significantly decreased whole brain glucose metabolism (measured with FDG) with the largest decrements in cerebellum and occipital cortex and the smallest in the thalamus. In contrast, alcohol intoxication caused a significant increase in [1-(11)C]acetate brain uptake (measured as standard uptake value, SUV), with the largest increases occurring in the cerebellum and the smallest in the thalamus. In heavy alcohol drinkers [1-(11)C]acetate brain uptake during alcohol challenge tended to be higher than in occasional drinkers (p<0.06) and the increases in [1-(11)C]acetate uptake in cerebellum with alcohol were positively associated with the reported amount of alcohol consumed (r=0.66, p<0.01). Our findings corroborate a reduction of brain glucose metabolism during intoxication and document an increase in brain acetate uptake. The opposite changes observed between regional brain metabolic decrements and regional increases in [1-(11)C]acetate uptake support the hypothesis that during alcohol intoxication the brain may rely on acetate as an alternative brain energy source and provides preliminary evidence that heavy alcohol exposures may facilitate the use of acetate as an energy substrate. These findings raise the question of the potential therapeutic benefits that increasing plasma acetate concentration (i.e. ketogenic diets) may have in alcoholics undergoing alcohol detoxification.

A forage-only diet alters the metabolic response of horses in training

Most athletic horses are fed a high-starch diet despite the risk of health problems. Replacing starch concentrate with high-energy forage would alleviate these health problems, but could result in a shift in major substrates for muscle energy supply from glucose to short-chain fatty acids (SCFA) due to more hindgut fermentation of fibre. Dietary fat inclusion has previously been shown to promote aerobic energy supply during exercise, but the contribution of SCFA to exercise metabolism has received little attention. This study compared metabolic response with exercise and lactate threshold (VLa4) in horses fed a forage-only diet (F) and a more traditional high-starch, low-energy forage diet (forage–concentrate diet - FC). The hypothesis was that diet F would increase plasma acetate concentration and increase VLa4 compared with diet FC. Six Standardbred geldings in race training were used in a 29-day change-over experiment. Plasma acetate, non-esterified fatty acids (NEFA), lactate, glucose and insulin concentrations and venous pH were measured in samples collected before, during and after a treadmill exercise test (ET, day 25) and muscle glycogen concentrations before and after ET. Plasma acetate concentration was higher before and after exercise in horses on diet F compared with diet FC, and there was a tendency (P = 0.09) for increased VLa4 on diet F. Venous pH and plasma glucose concentrations during exercise were higher in horses on diet F than diet FC, as was plasma NEFA on the day after ET. Plasma insulin and muscle glycogen concentrations were lower for diet F, but glycogen utilisation was similar for the two diets. The results show that a high-energy, forage-only diet alters the metabolic response to exercise and, with the exception of lowered glycogen stores, appears to have positive rather than negative effects on performance traits.

Effects of nutrient supply, plasma metabolites, and nutritional status of sows during transition on performance in the next lactation1

The aim of the present study was to evaluate the effects of nutrient supply, plasma metabolites, and nutritional status of sows during the transition from gestation to lactation on performance of piglets during the colostral period and throughout lactation. Forty second-parity sows were fed 1 of 4 gestation diets containing a different quantity of dietary fiber (171 to 404 g/kg of DM) from mating until d 108 of gestation. From d 108 of gestation until weaning (d 28 of lactation), sows were fed 1 of 5 lactation diets with a different quantity of dietary fat [3 or 8% with different proportions of medium- (MCFA) and long-chain fatty acids (LCFA)]. Blood was obtained by jugular venipuncture on d 108 and 112 of gestation and on d 1 of lactation, and concentrations of plasma glucose, NEFA, lactate, acetate, propionate, butyrate, and fatty acids were analyzed. Piglet growth and mortality were noted throughout lactation. Piglet mortality during the colostral period (0 to 24 h) was affected by the lactation diets and was positively related to sow backfat (d 108) and plasma lactate (d 112) and negatively related to mean piglet birth weight (P < 0.05). Mean piglet live BW gain (LWG) was recorded in the periods 0 to 24 h, 7 to 10 d, 14 to 17 d, and 17 to 28 d relative to parturition as indirect measures of colostrum yield (0 to 24 h), milk yield in early lactation (d 7 to 10), and at peak lactation (d 14 to 17 and d 17 to 28). Effects of gestation and lactation diets on studied sow traits were tested on selected days during the transition period and the next lactation, and tested statistically on separate days. The LWG in the colostral period was positively correlated with mean piglet birth weight (P < 0.001), plasma concentrations of propionate and MCFA (P < 0.05), and plasma acetate and butyrate (P < 0.1) on d 1 of lactation. The LWG in early lactation was inversely correlated with plasma lactate on d 108 (P < 0.05), plasma glucose on d 112, and backfat thickness on d 108 (P < 0.10). The LWG at peak lactation was positively correlated with MCFA intake of the sow on d 113 to 115 and backfat thickness on d 108 during the transition, and negatively correlated with intake of LCFA and ME intake on d 108 to 112 (P < 0.05). In conclusion, feeding and body condition of sows during the transition from gestation to lactation is important for neonatal piglet survival, lactation performance of sows, and piglet growth during the next lactation.

Effect of ensiled hop (Humulus lupulus L.) residues on plasma acetate turnover rate in sheep

An isotope dilution method using [1-(13)C]sodium acetate was applied to determine the effect of feeding ensiled hop (Humulus lupulus L.) residues on plasma acetate turnover rate in six adult crossbred sheep. The sheep were fed 63 g/kg body weight (BW)(0.75)/day of either mixed hay of orchardgrass (Dactylis glomerata L.) and reed canarygrass (Phalaris arundinacea L.) and round bale silage at 3:1 ratio (Hay-diet), or another where round bale silage was replaced by ensiled hop residues (Hop-diet) with a crossover design each of a 3-week period. The isotope dilution method was performed on day 21 of each dietary treatment. Dry matter digestibility was similar between diets, and nitrogen (N) digestibility was lower (P = 0.001) for Hop-diet than Hay-diet. However, N retention did not differ between diets. Plasma acetate concentration was lower (P = 0.04) for Hop-diet than Hay-diet, and the turnover rate of plasma acetate did not differ between diets. Plasma concentration of lactate and non-esterified fatty acids were similar between diets. Hop-diet was found almost comparable to Hay-diet on plasma acetate turnover rate in the present experimental conditions. Therefore, it could be concluded that hop residues partially could be used as an alternative to traditionally used round bale silage for rearing sheep.

Acetate supplementation attenuates lipopolysaccharide‐induced neuroinflammation

Glyceryl triacetate (GTA), a compound effective at increasing circulating and tissue levels of acetate was used to treat rats subjected to a continual 28 day intra-ventricular infusion of bacterial lipopolysaccharide (LPS). This model produces a neuroinflammatory injury characterized by global neuroglial activation and a decrease in choline acetyltransferase immunoreactivity in the basal forebrain. During the LPS infusion, rats were given a daily treatment of either water or GTA at a dose of 6 g/kg by oral gavage. In parallel experiments, free-CoA and acetyl-CoA levels were measured in microwave fixed brains and flash frozen heart, liver, kidney and muscle following a single oral dose of GTA. We found that a single oral dose of GTA significantly increased plasma acetate levels by 15 min and remained elevated for up to 4 h. At 30 min the acetyl-CoA levels in microwave-fixed brain and flash frozen heart and liver were increased at least 2.2-fold. The concentrations of brain acetyl-CoA was significantly increased between 30 and 45 min following treatment and remained elevated for up to 4 h. The concentration of free-CoA in brain was significantly decreased compared to controls at 240 min. Immunohistochemical and morphological analysis demonstrated that a daily treatment with GTA significantly reduced the percentage of reactive glial fibrillary acidic protein-positive astrocytes and activated CD11b-positive microglia by 40-50% in rats subjected to LPS-induced neuroinflammation. Further, in rats subjected to neuroinflammation, GTA significantly increased the number of choline acetyltransferase (ChAT)-positive cells by 40% in the basal forebrain compared to untreated controls. These data suggest that acetate supplementation increases intermediary short chain acetyl-CoA metabolism and that treatment is potentially anti-inflammatory and neuroprotective with regards to attenuating neuroglial activation and increasing ChAT immunoreactivity in this model.

Plasma acetate, gluconate and interleukin-6 profiles during and after cardiopulmonary bypass: a comparison of Plasma-Lyte 148 with a bicarbonate-balanced solution

IntroductionAs even small concentrations of acetate in the plasma result in pro-inflammatory and cardiotoxic effects, it has been removed from renal replacement fluids. However, Plasma-Lyte 148 (Plasma-Lyte), an electrolyte replacement solution containing acetate plus gluconate is a common circuit prime for cardio-pulmonary bypass (CPB). No published data exist on the peak plasma acetate and gluconate concentrations resulting from the use of Plasma-Lyte 148 during CPB.MethodsThirty adult patients were systematically allocated 1:1 to CPB prime with either bicarbonate-balanced fluid (24 mmol/L bicarbonate) or Plasma-Lyte 148. Arterial blood acetate, gluconate and interleukin-6 (IL-6) levels were measured immediately before CPB (T1), three minutes after CPB commencement (T2), immediately before CPB separation (T3), and four hours post separation (T4).ResultsAcetate concentrations (normal 0.04 to 0.07 mmol/L) became markedly elevated at T2, where the Plasma-Lyte group (median 3.69, range (2.46 to 8.55)) exceeded the bicarbonate group (0.16 (0.02 to 3.49), P < 0.0005). At T3, levels had declined but the differential pattern remained apparent (Plasma-Lyte 0.35 (0.00 to 1.84) versus bicarbonate 0.17 (0.00 to 0.81)). Normal circulating acetate concentrations were not restored until T4. Similar gluconate concentration profiles and inter-group differences were seen, with a slower T3 decay. IL-6 increased across CPB, peaking at T4, with no clear difference between groups.ConclusionsUse of acetate containing prime solutions result in supraphysiological plasma concentrations of acetate. The use of acetate-free prime fluid in CPB significantly reduced but did not eliminate large acetate surges in cardiac surgical patients. Complete elimination of acetate surges would require the use of acetate free bolus fluids and cardioplegia solutions.Trial registrationAustralia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000267055

Intermediary Metabolism of Plasma Acetic Acid, Glucose and Protein in Sheep Fed a Rice Straw-based Diet

The present study was conducted to determine plasma acetate, glucose and protein metabolism using dilution of isotopes [[1- 13 C]Na acetate, [U- 13 C]glucose and [1- 13 C]leucine (Leu)] in sheep fed rice straw (Oriza japonica L.). Four sheep were assigned to either rice straw (RS-diet) or mixed hay (MH-diet) with a crossover design. Nitrogen (N) intake and N digestibility were lower (p = 0.002 and p = 0.02, respectively) for RS-diet than MH-diet, but N retention did not differ (p>0.10) between the diets. Concentrations of rumen acetate tended to be lower (p = 0.07), and propionate was higher (p = 0.02) for RS-diet than MH-diet. Concentrations of plasma lactate, non-esterified fatty acids, Leu and α-ketoisocaproic acid did not differ (p>0.10) between the diets, but plasma glucose and urea concentrations were lower (p = 0.01 and p = 0.003, respectively) for RS-diet than MH-diet. Turnover rate of plasma acetate did not differ (p = 0.39) between the diets, and plasma glucose and Leu turnover rates were numerically lower (p = 0.15 and p = 0.14, respectively) for RS-diet than MH-diet. Whole body protein synthesis and degradation did not differ (p>0.10) between the diets. Thus it can be concluded that the intermediary metabolism of acetate, glucose and protein on rice straw is comparable to mixed hay in sheep.

Evaluation of Cerebral Acetate Transport and Metabolic Rates in the Rat Brain in vivo Using 1H-[13C]-NMR

Acetate is a well-known astrocyte-specific substrate that has been used extensively to probe astrocytic function in vitro and in vivo. Analysis of amino acid turnover curves from (13)C-acetate has been limited mainly for estimation of first-order rate constants from exponential fitting or calculation of relative rates from steady-state (13)C enrichments. In this study, we used (1)H-[(13)C]-Nuclear Magnetic Resonance spectroscopy with intravenous infusion of [2-(13)C]acetate-Na(+) in vivo to measure the cerebral kinetics of acetate transport and utilization in anesthetized rats. Kinetics were assessed using a two-compartment (neuron/astrocyte) analysis of the (13)C turnover curves of glutamate-C4 and glutamine-C4 from [2-(13)C]acetate-Na(+), brain acetate levels, and the dependence of steady-state glutamine-C4 enrichment on blood acetate levels. The steady-state enrichment of glutamine-C4 increased with blood acetate concentration until 90% of plateau for plasma acetate of 4 to 5 mmol/L. Analysis assuming reversible, symmetric Michaelis-Menten kinetics for transport yielded 27+/-2 mmol/L and 1.3+/-0.3 micromol/g/min for K(t) and T(max), respectively, and for utilization, 0.17+/-0.24 mmol/L and 0.14+/-0.02 micromol/g/min for K(M_util) and V(max_util), respectively. The distribution space for acetate was only 0.32+/-0.12 mL/g, indicative of a large excluded volume. The astrocytic and neuronal tricarboxylic acid cycle fluxes were 0.37+/-0.03 micromol/g/min and 1.41+/-0.11 micromol/g/min, respectively; astrocytes thus comprised approximately 21%+/-3% of total oxidative metabolism.

The effect of ethanol and its metabolism on fibrinolysis

The role of ethanol metabolism in possible haemostatic cardioprotective effects has not yet been determined. To this end, we investigated the effect of a moderate dose of ethanol (35 g) and its metabolism, on haemostatic variables over 14 hours (h). Eighteen Caucasian males participated in a placebo-controlled, randomised, cross-over study. Blood was collected prior to alcohol consumption, and at 10 time points for 14 h. Blood ethanol peaked at 1 h and was cleared after 8 h following ethanol consumption, significantly increasing plasma acetate (p=0.0028). Ethanol did not influence the coagulation factors significantly. PAI-1act increased (p<0.0001) and tPAact (p=0.047) decreased following alcohol consumption, reaching maximum (0.69 to 22.2 IU/ml) and minimum (0.88 to 0.33 IU/ml) levels at 5 h, respectively. Significantly increased plasma clot lysis times (46.8 to 67.6 minutes) and reduced global fibrinolytic capacity of whole blood, measured as D-dimer production during incubation of blood clots (2.26 to 0.29 μg/ml), were found at 5 h. Except for PAI-1act (borderline significance; p=0.05), there was no significant difference in the fibrinolytic markers between the two groups the following morning. Moderate ethanol consumption resulted in a significant temporary fibrinolysis inhibition. Any protective effects of moderate ethanol consumption on cardiovascular disease do not appear to be due to improvement in fibrinolytic potential within the first 14 h following consumption. The use of global fibrinolytic assays is recommended for determining the true effect of ethanol on fibrinolysis.

Adaptation of colonic fermentation and glucagon-like peptide-1 secretion with increased wheat fibre intake for 1 year in hyperinsulinaemic human subjects

High cereal fibre intake is associated with reduced risk for type 2 diabetes, but wheat fibre had little or no effect on glycaemic control or oral glucose tolerance in clinical trials lasting 4-12 weeks. To explain this discrepancy, we hypothesised that colonic adaptation to increased wheat fibre intake takes many months but eventually results in increased SCFA production and glucagon-like peptide-1 (GLP-1) secretion. Thus, the primary objective was to determine the time-course of the effects of increased wheat fibre intake on plasma acetate, butyrate and GLP-1 concentrations in hyperinsulinaemic human subjects over 1 year. Subjects with fasting plasma insulin >or= 40 pmol/l were randomly assigned by computer to receive either a high-wheat fibre cereal (fibre group; 24 g fibre/d; twenty assigned; six dropped out, fourteen included) or a low-fibre cereal (control group; twenty assigned; six dropped-out, fourteen included) daily for 1 year. Acetate, butyrate and GLP-1 were measured during 8 h metabolic profiles performed every 3 months. There were no differences in body weight in the fibre group compared with the control group. After 9 months baseline-adjusted mean 8 h acetate and butyrate concentrations were higher on the high-fibre than the control cereal (P < 0.05). After 12 months on the high-fibre cereal, baseline-adjusted mean plasma GLP-1 was 1.3 (95 % CI 0.4, 2.2) pmol/l (P < 0.05) higher than at baseline (about 25 % increase) and 1.4 (95 % CI 0.1, 2.7) pmol/l (P < 0.05) higher than after 12 months on control. It is concluded that wheat fibre increased SCFA production and GLP-1 secretion in hyperinsulinaemic humans, but these effects took 9-12 months to develop. Since GLP-1 may increase insulin sensitivity and secretion, these results may provide a mechanism for the epidemiological association between high cereal fibre intake and reduced risk for diabetes.

Plasma concentration of anti‐diuretic hormone and urine volume in response to intraruminal administration of acetate, propinata and butyrate in suckling calves

Acetate, propionate, and butyrate were intraruminally administered to dry feed-fed suckling calves to evaluate their effects on plasma ketone bodies, anti-diuretic hormone (ADH) concentrations, and urine volume. Four male Holstein calves (5-7 weeks old) were given 1.0 L of warm water or 0.5 mole of one of the acids in 1.0 L of warm water. A 4 x 4 Latin square design was adopted for the experiment. The acetate group showed significantly higher plasma acetate concentrations than the other three groups between 0.25 h and 2.0 h after administration (P < 0.01). Plasma glucose concentrations did not differ markedly among the groups. The butyrate group showed significantly higher plasma ketone body concentrations than the other three groups until the end of the experiment (P < 0.01). Plasma ADH concentrations quickly rose in the butyrate group and remained significantly higher than in the other three groups from 0.25 h to 2.5 h after administration (P < 0.05). In accordance with the elevation of plasma ADH levels, the butyrate group showed decreases in urine volume and increases in urine osmolarity (P < 0.05). Plasma osmolarity and hematocrit values (Ht) were not different among the groups. These results suggest that the administration of acetate and propionate had little effect on ADH secretion.

Acetate transport and utilization in the rat brain.

Acetate, a glial-specific substrate, is an attractive alternative to glucose for the study of neuronal-glial interactions. The present study investigates the kinetics of acetate uptake and utilization in the rat brain in vivo during infusion of [2-13C]acetate using NMR spectroscopy. When plasma acetate concentration was increased, the rate of brain acetate utilization (CMR(ace)) increased progressively and reached close to saturation for plasma acetate concentration > 2-3 mM, whereas brain acetate concentration continued to increase. The Michaelis-Menten constant for brain acetate utilization (K(M)(util) = 0.01 +/- 0.14 mM) was much smaller than for acetate transport through the blood-brain barrier (BBB) (K(M)(t) = 4.18 +/- 0.83 mM). The maximum transport capacity of acetate through the BBB (V(max)(t) = 0.96 +/- 0.18 micromol/g/min) was nearly twofold higher than the maximum rate of brain acetate utilization (V(max)(util) = 0.50 +/- 0.08 micromol/g/min). We conclude that, under our experimental conditions, brain acetate utilization is saturated when plasma acetate concentrations increase above 2-3 mM. At such high plasma acetate concentration, the rate-limiting step for glial acetate metabolism is not the BBB, but occurs after entry of acetate into the brain.

Responses of Plasma Acetate Metabolism to Hop (Humulus lupulus L.) in Sheep

An isotope dilution method using [1-(13)C]sodium (Na) acetate was conducted to determine the effect of feeding hop (Humulus lupulus L.) residues on plasma acetate metabolism in six adult crossbred sheep. The sheep were fed 63 g/kg BW(0.75)/d of either mixed hay (MH-diet) of orchardgrass (Dactylis glomerata L.) and reed canarygrass (Phalaris arundinacea L.) at a 60:40 ratio or MH-diet and hop-residues (Hop-diet) at 85:15 ratio with a crossover design for each of 3 week period. The isotope dilution method using single injection of [1-(13)C]Na acetate was performed thrice; before feeding (BF), 2 h after feeding (2F) and 4 h after feeding (4F), on the 21(st) day of each dietary treatment. Plasma acetate concentration tended to increase (P=0.06) and turnover rate was numerically higher (P=0.16) for MH-diet than Hop-diet. Plasma glucose, NEFA, VFA and lactic acid concentrations were similar between dietary treatments. In both the diets, although plasma concentration of acetate did not change, turnover rate increased significantly (P=0.02) 2F than BF. Hop-residues did not show any negative impacts on acetate metabolism as well as physiology of animals in the present experimental conditions, hence thereby it could be used as an alternative to MH-diet for rearing sheep.

Chicory increases acetate turnover, but not propionate and butyrate peripheral turnovers in rats.

Chicory roots are rich in inulin that is degraded into SCFA in the caecum and colon. Whole-body SCFA metabolism was investigated in rats during food deprivation and postprandial states. After 22 h of food deprivation, sixteen rats received an IV injection of radioactive 14C-labelled SCFA. The volume of distribution and the fractional clearance rate of SCFA were 0.25-0.27 litres/kg and 5.4-5.9 %/min, respectively. The half-life in the first extracellular rapidly decaying compartment was between 0.9 and 1.4 min. After 22 h of food deprivation, another seventeen rats received a primed continuous IV infusion of 13C-labelled SCFA for 2 h. Isotope enrichment (13C) of SCFA was determined in peripheral arterial blood by MS. Peripheral acetate, propionate and butyrate turnover rates were 29, 4 and 0.3 micromol/kg per min respectively. Following 4 weeks of treatment with chicory root or control diets, eighteen fed rats received a primed continuous IV infusion of 13C-labelled SCFA for 2 h. Intestinal degradation of dietary chicory lowered caecal pH, enhanced caecal and colonic weights, caecal SCFA concentrations and breath H2. The diet with chicory supplementation enhanced peripheral acetate turnover by 25 % (P = 0.017) concomitant with an increase in plasma acetate concentration. There were no changes in propionate or butyrate turnovers. In conclusion, by setting up a multi-tracer approach to simultaneously assess the turnovers of acetate, propionate and butyrate it was demonstrated that a chronic chicory-rich diet significantly increases peripheral acetate turnover but not that of propionate or butyrate in rats.

The effect of oral sodium acetate administration on plasma acetate concentration and acid-base state in horses

AimSodium acetate (NaAcetate) has received some attention as an alkalinizing agent and possible alternative energy source for the horse, however the effects of oral administration remain largely unknown. The present study used the physicochemical approach to characterize the changes in acid-base status occurring after oral NaAcetate/acetic acid (NAA) administration in horses.MethodsJugular venous blood was sampled from 9 exercise-conditioned horses on 2 separate occasions, at rest and for 24 h following a competition exercise test (CET) designed to simulate the speed and endurance test of 3-day event. Immediately after the CETs horses were allowed water ad libitum and either: 1) 8 L of a hypertonic NaAcetate/acetic acid solution via nasogastric tube followed by a typical hay/grain meal (NAA trial); or 2) a hay/grain meal alone (Control trial).ResultsOral NAA resulted in a profound plasma alkalosis marked by decreased plasma [H+] and increased plasma [TCO2] and [HCO3-] compared to Control. The primary contributor to the plasma alkalosis was an increased [SID], as a result of increased plasma [Na+] and decreased plasma [Cl-]. An increased [Atot], due to increased [PP] and a sustained increase in plasma [acetate], contributed a minor acidifying effect.ConclusionIt is concluded that oral NaAcetate could be used as both an alkalinizing agent and an alternative energy source in the horse.

Effects of Dietary Starch and Sucrose on Tissue Responsiveness and Sensitivity to Insulin in Goats Fed a High-concentrate Diet

A glucose clamp technique was used to compare dietary starch (ST), starch plus sucrose (ST+SU) and sucrose (SU) with regard to the effect on tissue responsiveness and sensitivity to insulin in intact adult male goats. The goats were fed diets containing 1.2 times of ME and CP for maintenance requirements twice daily for 21 d. Of the energy intake, 30% was offered with ST, ST+SU or SU for the respective diets, and 70% as alfalfa hay, ground corn and ground soybean meal at the respective weight ratio of 1, 1, and 0.3 for all diets. Tissue responsiveness and sensitivity to insulin were evaluated using a hyperinsulinemic euglycemic clamp technique with four levels of insulin infusion beyond 13 h after feeding. The concentrations of plasma metabolites and insulin were also determined at 3, 6 and 13 h after feeding to evaluate the effects of different carbohydrates on metabolic states in the body. Plasma glucose concentration was higher (p = 0.01) for SU diet than for ST and ST+SU diets. Increasing SU intake decreased (p<0.01) plasma acetate concentration across the time. At 3 h but not 6 and 13 h after feeding, high lactate (p = 0.01), and non-significant high propionate (p = 0.14) and low urea nitrogen (p = 0.19) concentrations were observed in plasma on SU compared with ST and ST+SU diets. Plasma insulin concentration was not different (p = 0.44) between ST and SU fed animals. In the glucose clamp experiment, considering the effects on the maximal glucose infusion rate (tissue responsiveness to insulin, p = 0.54) and the plasma insulin concentration at half-maximal glucose infusion rate (insulin sensitivity, p = 0.54), SU was not different from ST. It is concluded that SU may not be greatly different from ST with regard to the effect on tissue responsiveness and sensitivity to insulin in adult goats when fed twice daily as part of a high-concentrate diet. The possible greater effects of SU on plasma metabolites concentrations at 3 h than at 6 and 13 h after feeding suggest that a lack of persistency of SU effects during the postfeeding period may be associated with the poor response to SU in insulin action.

Solid‐phase microextraction method for carbon isotopic analysis of volatile carboxylic acids in human plasma by gas chromatography/combustion/isotope ratio mass spectrometry

A new analytical method is described for the determination of the physiological concentration and low-level enrichment of (13)C-short-chain volatile organic acids (SCVAs) (e.g. (13)C-acetate and (13)C-butyrate) in human plasma. This two-step method involves solid-phase microextraction (SPME) coupled to gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS) without any organic solvents or derivatizing agents. Two SCVA extraction methods were compared using a carboxen/polydimethylsiloxane fiber: headspace sampling (HS) and liquid sampling (LS) SPME. The influences of extraction temperature and time were tested to optimize the adsorption of SCVAs onto the fiber. The comparison of the peak area responses of the acids in the two adsorption methods showed better sensitivity in the human physiological concentration range in the LS mode than in the HS mode. The accuracy of isotopic enrichment measurement was determined using plasma spiked with (13)C-acetate and (13)C-butyrate solution from 0 to 1 mol percent excess (MPE). The linearity and repeatability (RSD < 5%) were measured in LS mode. Plasma SCVA concentrations were also determined relative to 3-methylvalerate (internal standard). Linearity and repeatability were observed from 0 to 400 microM for acetate, from 0 to 20 microM for propionate, and from 0 to 10 microM for butyrate. This method was also used to determine plasma acetate production obtained from lactulose (an undigestible disaccharide) fermentation in one healthy volunteer over 3 h. The acetate concentration increased twofold, 2 h after oral lactulose intake. These results are in agreement with the data obtained by GC/MS in healthy volunteers and obese adults following a lactulose intake by using higher amounts of labelled tracers.SPME coupled with GC/C/IRMS can be used to analyze (13)C-SCVAs at low enrichment (<0.5 MPE) within the physiological concentration measured in human plasma.

Effects of Supplementing Concentrates Differing in Carbohydrate Composition in Veal Calf Diets: II. Rumen Development

The objective of this experiment was to examine the effects of concentrates in feed, differing in carbohydrate source, on the rumen development of veal calves. For this purpose, 160 male Holstein Friesian×Dutch Friesian crossbred calves were used in a complete randomized block design with a 5×2 factorial arrangement. Dietary treatments consisted of 1) a milk replacer control, 2) a pectin-based concentrate, 3) a neutral detergent fiber-based concentrate, 4) a starch-based concentrate, and 5) a mixed concentrate (equal amounts of the concentrates in treatments 2, 3, and 4). Concentrate diets were provided as pellets in addition to a commercial milk replacer. Calves were euthanized at either 8 or 12 wk of age. Plasma acetate and β-hydroxybutyrate (BHBA) were measured as indicators of rumen development. Empty rumen weight was determined, and wall samples were taken at slaughter. In most calves, a poorly developed rumen mucosa was observed. Coalescing rumen papillae with embedded hair, feed particles, and cell debris were found in all calves fed the concentrate diets. Calves fed concentrates had significantly heavier rumens than calves fed the control diet. In the dorsal location of the rumen, calves fed concentrate diets showed an increased ratio of mucosa to serosa length compared with calves fed the control diet, whereas in the ventral location only, calves fed the pectin and mixed diets showed larger ratios of mucosa to serosa length. Mucosa thickness and muscle thickness were greater in the ventral and dorsal locations of the rumen, respectively. In both locations, the NDF diet resulted numerically in the lowest mucosa thickness and highest muscle thickness among the concentrate treatments. At 8 wk, calves fed the concentrate diets had higher plasma acetate concentrations than calves on the control treatment. However, at 12 wk, only NDF-fed calves showed significantly higher plasma acetate concentrations. The plasma BHBA concentrations of calves at 8 wk of age fed the pectin and mixed diets were higher than those of the control diet-fed calves. At 12 wk, no differences in BHBA concentrations were observed among treatments. Results of a principal component analysis indicated that, in addition to rumen volatile fatty acid concentrations, other factors were likely to affect rumen development, and that the relationships between rumen development and individual types of volatile fatty acids present in the rumen liquor were similar. Also, variations in rumen development coincided with variations in plasma acetate and BHBA concentrations.

Sodium acetate ingestion perturbs substrate utilisation at rest and during the early stages of prolonged exercise in man

Sodium acetate administration has been shown to increase muscle acetyl-CoA and acetylcarnitine content at rest and during the early stages of exercise. We therefore investigated the effect of sodium acetate ingestion at rest on subsequent substrate utilisation during prolonged exercise. With local ethics approval six healthy males ingested either sodium acetate (NaAc) or sodium bicarbonate (NaHCO3) at a dose of 4 mmol.kg−1 body mass in a randomised order over 90 min prior to 120 min of exercise at 50% V̇O2max. NaAc ingestion decreased resting fat oxidation (0.09 ± 0.02 vs. 0.07 ± 0.02 g.min−1 pre- and post-ingestion respectively, P<0.05) with no effect upon carbohydrate utilisation. In contrast, NaHCO3 ingestion did not affect substrate utilisation at rest. Fat and CHO oxidation increased in both trials when exercise was undertaken, but fat oxidation was lower (0.16 ± 0.10 vs. 0.30 ± 0.10 g.min−1, P<0.05) and carbohydrate oxidation higher (1.75 ± 0.36 vs. 1.50 ± 0.23 g.min−1, P<0.05) in the NaAc compared with the NaHCO3 trial during the first 15 min of exercise. Plasma acetate concentration had returned to baseline after 30 min of exercise in the NaAc trial with no difference in either fat or carbohydrate utilisation between the trials over the last 90 min of exercise. These results demonstrate that increasing plasma acetate concentration suppresses fat oxidation at rest and at the onset of exercise possibly due to changes in acetyl group availability.