Albumin and fibrinogen kinetics in sepsis: a prospective observational study.

BACKGROUND: The measurement of circulating substrate concentrations does not provide information about substrate kinetics. It, therefore, remains unclear if a decrease in plasma concentration of albumin, as seen during critical illness, is a consequence of suppressed production in the liver or increased peripheral clearance. In this study, using stable isotope tracer infusions, we measured albumin and fibrinogen kinetics in septic patients and in a control group of non-septic subjects. METHODS: With the approval from the institutional Research Ethics Board and after obtaining written informed consent from patients or their substitute decision maker, mechanically ventilated patients with sepsis and patients scheduled for elective coronary artery bypass grafting were enrolled. Patients in the non-sepsis group were studied on the day before surgery. The stable isotope L-[ring-2H5]phenylalanine was used to measure absolute synthesis rates (ASR) of albumin and fibrinogen. A priming dose of L-[ring-2H5]phenylalanine (4 µmol/kg) was given followed by a six-hour infusion at a rate of 0.15 µmol/kg/min. At baseline and hourly thereafter, blood was drawn to measure isotope enrichments by gas chromatography/mass spectrometry. Very low density lipoprotein apolipoprotein-B 100 isotopic enrichment was used to represent the isotopic enrichment of the phenylalanine precursor pool from which the liver synthesizes proteins. Plasma albumin and fibrinogen concentrations were also measured. RESULTS: Mean plasma albumin in septic patients was decreased when compared to non-septic patients, while synthesis rates were comparable. Mean plasma fibrinogen and ASR in septic patients was increased when compared to non-septic patients. In non-septic patients, no statistically significant correlation between plasma albumin and ASR was observed but plasma fibrinogen significantly correlated with ASR. In septic patients, plasma albumin and fibrinogen significantly correlated with ASR. CONCLUSIONS: While septic patients showed lower plasma albumin levels than non-septic patients, albumin synthesis was similar in the two groups suggesting that hypoalbuminemia during sepsis was not caused by suppressed hepatic production but a result of enhanced clearance from the circulation. Hyperfibrinogenemia in septic patients was a consequence of increased fibrinogen production. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02865408 (registered on August 12, 2016) and ClinicalTrials.gov: NCT02549443 (registered on September 15, 2015).

Intranasal administration of 40 and 80 units of insulin does not cause hypoglycemia during cardiac surgery: a randomized controlled trial.

PURPOSE: Intranasal insulin administration may improve cognitive function in patients with dementia and may prevent cognitive problems after surgery. Although the metabolic effects of intranasal insulin in non-surgical patients have been studied, its influence on glucose concentration during surgery is unknown. METHODS: We conducted a randomized, double-blind, placebo-contolled trial in patients scheduled for elective cardiac surgery. Patients with type 2 diabetes mellitus (T2DM) and non-T2DM patients were randomly allocated to one of three groups (normal saline, 40 international units [IU] of intranasal insulin, and 80 IU intranasal insulin). Insulin was given after the induction of general anesthesia. Glucose and plasma insulin concentrations were measured in ten-minute intervals during the first hour and every 30 min thereafter. The primary outcome was the change in glucose concentration 30 min after intranasal insulin administration. RESULTS: A total of 115 patients were studied, 43 of whom had T2DM. In non-T2DM patients, 40 IU intranasal insulin did not affect glucose concentration, while 80 IU intranasal insulin led to a statistically significant but not clinically important decrease in blood glucose levels (mean difference, 0.4 mMol·L-1; 95% confidence interval, 0.1 to 0.7). In T2DM patients, neither 40 IU nor 80 IU of insulin affected glucose concentration. No hypoglycemia (< 4.0 mMol·L-1) was observed after intranasal insulin administration in any patients. In non-T2DM patients, changes in plasma insulin were similar in the three groups. In T2DM patients, there was an increase in plasma insulin concentrations ten minutes after administration of 80 IU of intranasal insulin compared with saline. CONCLUSIONS: In patients with and without T2DM undergoing elective cardiac surgery, intranasal insulin administration at doses as high as 80 IU did not cause clinically important hypoglycemia. TRIAL REGISTRATION: www.ClinicalTrials.gov (NCT02729064); registered 5 April 2016.

RéSUMé: OBJECTIF: L'administration intranasale d'insuline pourrait améliorer la fonction cognitive des patients souffrant de démence et pourrait prévenir les problèmes cognitifs après une chirurgie. Bien que les effets métaboliques de l'insuline intranasale chez les patients non chirurgicaux aient été étudiés, son influence sur la glycémie pendant une chirurgie est inconnue. MéTHODE: Nous avons réalisé une étude randomisée, à double insu, contrôlée par placebo auprès de patients devant subir une chirurgie cardiaque non urgente. Des patients atteints de diabète de type 2 et des patients non diabétiques ont été randomisés dans l'un de trois groupes (solution physiologique salée, 40 unités internationales [UI] d'insuline intranasale et 80 UI d'insuline intranasale). La solution intranasale a été administrée après l'induction de l'anesthésie générale. Les concentrations de glucose et d'insuline plasmatique ont été mesurées à des intervalles de dix minutes pendant la première heure et toutes les 30 minutes par la suite. Le critère d'évaluation principal était le changement de glycémie 30 min après l'administration intranasale d'insuline. RéSULTATS: Un total de 115 patients ont été étudiés, dont 43 souffraient de diabète de type 2. Chez les patients non diabétiques, 40 UI d'insuline intranasale n'ont pas affecté la glycémie, alors que 80 UI d'insuline intranasale ont entraîné une réduction statistiquement significative mais non cliniquement importante de la glycémie (différence moyenne, 0,4 mMol·L−1; intervalle de confiance de 95 %, 0,1 à 0,7). Chez les patients diabétiques, ni 40 UI ni 80 UI d'insuline n'ont affecté la glycémie. Aucune hypoglycémie (< 4,0 mMol·L−1) n'a été observée après administration intranasale d'insuline chez les patients diabétiques ou non diabétiques. Chez les patients non diabétiques, les changements de l'insuline plasmatique étaient semblables dans les trois groupes. Chez les patients diabétiques, une augmentation des concentrations d'insuline plasmatique a été observée dix minutes après l'administration de 80 UI d'insuline intranasale comparée à la solution saline. CONCLUSION: Chez les patients diabétiques et non diabétiques subissant une chirurgie cardiaque non urgente, l'administration intranasale d'insuline à des doses allant jusqu'à 80 UI n'a pas causé d'hypoglycémie cliniquement importante. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT02729064); enregistrée le 5 avril 2016.

Plasma levels of one-carbon metabolism nutrients in women with anorexia nervosa.

OBJECTIVE: People who are ill with anorexia nervosa (AN) show altered availability of key plasma nutrients. However, little is known about the patterning of alterations that occurs across diverse nutrients during active phases of illness or about the persistence of any such alterations following remission of illness. METHOD: We compared plasma levels of one-carbon metabolism nutrients across women with active AN (AN-Active: n = 53), in remission from AN (AN-Remitted: n = 40), or who had no eating-disorder history (NED: n = 36). We also tested associations between body mass index (BMI) changes and changes in pre- to posttreatment nutrient levels, and explored the association between nutrient levels, on the one hand, and BMI and eating symptoms, on the other. Choline, betaine, and methionine were analyzed using mass spectrometry. Folate and B12 were analyzed using the AccuBind® ELISA kit. Eating-disorder symptoms were assessed by interview and self-report. RESULTS: Compared to NED individuals, AN-Active individuals exhibited significantly elevated B12 and (less-reliably) betaine. In AN-Active individuals, lower BMI was associated with higher B12. DISCUSSION: The observed alterations run contrary to the intuition that plasma nutrient levels should be directly responsive to nutritional status and suggest, instead, the existence of compensatory adaptations to malnutrition in individuals with active AN. Further study is required to clarify mechanisms that underlie such effects.

Accuracy of blood glucose measurements using the NOVA StatStrip® glucometer during cardiac surgery: a prospective observational study.

PURPOSE: The Nova StatStrip® Glucose Hospital Meter System (Nova Biomedical, Waltham, MA, USA) is United States Food and Drug Administration approved for point-of-care use in critically ill patients, but its use during cardiac surgery has not been evaluated. In this study, we compare glucose values obtained during cardiac surgery by StatStrip® with values obtained by a blood gas analyzer. METHODS: Blood glucose concentrations were analyzed in 121 patients by the StatStrip point- of-care test (POCT) glucose monitor and the GEM® Premier™ 3000 blood gas analyzer (Instrumentation Laboratory Company, Bedford MA, USA). Arterial blood samples were taken at baseline (before surgery), before cardiopulmonary bypass (CPB), during early and late CPB, and 30 min after CPB. Accuracy of the StatStrip glucometer was analyzed using the Clinical and Laboratory Standards Institute (CLSI) POCT12-A3 criteria (criterion 1; 95% of samples should be ± 0.66 mMol·L-1 of reference glucose values < 5.5 mMol·L-1 and ± 12.5% for reference glucose values > 5.5 mMol·L-1, criterion 2; 98% of samples should be ± 0.83 mMol·L-1 of reference glucose values < 4.1 mMol·L-1 or 20% of the reference glucose for values > 4.1 mMol·L-1). RESULTS: The accuracy of StatStrip glucose measurements at baseline (99%, 100%) and before CPB (95%, 98%), but not during (early: 84%, 97%; late: 83%, 96%) and after (92%, 100%) CPB, satisfied the CLSI POCT12-A3 criteria. CONCLUSION: Arterial blood glucose measurement by StatStrip was accurate before CPB, but lacked accuracy during and after CPB. Glucose values should be interpreted with caution when intensive glucose control protocols are being used during cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02729064); registered 5 April, 2016.

RéSUMé: OBJECTIF: Le glucomètre hospitalier StatStrip® de Nova (Nova Biomedical, Waltham, MA, É.-U.) est approuvé par la FDA (Food and Drug Administration) américaine pour une utilisation au chevet chez les patients en état critique, mais son utilisation n'a pas été évaluée en chirurgie cardiaque. Dans cette étude, nous avons comparé les valeurs glycémiques obtenues par le lecteur StatStrip® et les valeurs obtenues par un analyseur des gaz du sang pendant une chirurgie cardiaque. MéTHODE: Les concentrations glycémiques de 121 patients ont été analysées en utilisant le moniteur glycémique StatStrip et l'analyseur de gaz sanguins GEM® Premier™ 3000 (Instrumentation Laboratory Company, Bedford, MA, É.-U.). Des échantillons de sang artériel ont été prélevés avant la chirurgie, avant la circulation extracorporelle (CEC), au début et à la fin de la CEC et 30 min après la CEC. La précision du glucomètre StatStrip a été analysée à l'aide des critères de l'Institut des normes cliniques et de laboratoire (Clinical and Laboratory Standards Institute (CLSI)) POCT12-A3 (1er critère; 95 % des échantillons doivent être à l'intérieur de ± 0,66 mMol·L−1 des valeurs glycémiques de référence < 5,5 mMol·L−1 et ± 12,5 % pour les valeurs glycémiques de référence > 5,5 mMol·L−1, 2ème critère; 98 % des échantillons doivent être à l'intérieur de ± 0,83 mMol·L−1 des valeurs glycémiques de référence < 4,1 mMol·L−1 ou 20 % du taux glycémique de référence pour les valeurs > 4,1 mMol·L−1). RéSULTATS: La précision des mesures glycémiques prises par le StatStrip avant l'opération (99 %, 100 %) et avant la CEC (95 %, 98 %), mais non durant (début : 84 %, 97 %; fin : 83 %, 96 %) et après (92 %,100 %) la CEC, respectait les critères POCT12-A3 du CLSI. <0} CONCLUSION: La mesure de la glycémie artérielle réalisée avec le StatStrip était précise avant la CEC mais a manqué de précision pendant et après la CEC. Les valeurs glycémiques devraient donc être interprétées avec prudence lorsque des protocoles intensifs de contrôle glycémique sont utilisés pendant une chirurgie cardiaque. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT02729064); enregistrée le 5 avril 2016.

Hyperinsulinemic-normoglycemic clamp administered together with amino acids induces anabolism after cardiac surgery.

Cardiac surgery triggers an inflammatory stress response, leading to protein catabolism, a process that even high-dose insulin therapy alone cannot reverse. To determine whether hyperinsulinemic-normoglycemic clamp and perioperative amino acid (AA) supplementation improves whole body protein balance, 20 patients scheduled for elective coronary artery bypass grafting surgery were randomly assigned to have intra- and postoperative hyperinsulinemic-normoglycemic clamp, with or without intravenous AA supplementation. Primed continuous infusions of [6,6-2H2]glucose and l-[1-13C]leucine were used to quantify whole body protein and glucose metabolism before and after surgery. Adipose tissue and serum cytokines were also analyzed to measure their responsiveness to the anabolic effect of AA administration. During hyperinsulinemic-normoglycemic clamp, AA supplementation successfully stimulated whole body protein synthesis, resulting in a positive whole body protein balance after surgery (insulin: -13.6 ± 4.5 vs. insulin + AA: 2.1 ± 5.4 µmol·kg-1·h-1, P < 0.001). Endogenous glucose production was equally suppressed in both groups (insulin: 0.0 ± 3.8 vs. insulin + AA 1.6 ± 1.6 µmol·kg-1·min-1, P = 0.230). AA supplementation led to significant changes in serum and tissue IL-6 (insulin: 246.6 ± 111.2 vs. insulin + AA: 124.5 ± 79.3 pg/ml, P = 0.011). In conclusion, hyperinsulinemic-normoglycemic clamp technique, together with AA supplementation, can induce an anabolic state after open-heart surgery, as quantified by a positive whole body protein balance.

Inactivation of the ubiquitin-specific protease 19 deubiquitinating enzyme protects against muscle wasting.

The ubiquitin system plays a critical role in muscle wasting. Previous work has focused on the roles of ubiquitination. However, a role for deubiquitination in this process has not been established. Because ubiquitin-specific protease (USP)19 deubiquitinating enzyme is induced in skeletal muscle in many catabolic conditions, we generated USP19 knockout (KO) mice. These mice lost less muscle mass than wild-type (WT) animals in response to glucocorticoids, a common systemic cause of muscle atrophy as well as in response to denervation, a model of disuse atrophy. KO mice retained more strength and had less myofiber atrophy with both type I and type IIb fibers being protected. Rates of muscle protein synthesis were similar in WT and KO mice, suggesting that the sparing of atrophy was attributed to suppressed protein degradation. Consistent with this, expression of the ubiquitin ligases MuRF1 and MAFbx/atrogin-1 as well as several autophagy genes was decreased in the muscles of catabolic KO mice. Expression of USP19 correlates with that of MuRF1 and MAFbx/atrogin-1 in skeletal muscles from patients with lung cancer or gastrointestinal cancer, suggesting that USP19 is involved in human muscle wasting. Inhibition of USP19 may be a useful approach to the treatment of many muscle-wasting conditions.

Colitis, independent of macronutrient intake, compromises bone structure and strength in growing piglets.

BACKGROUND: Deterioration in bone health is a concern in managing pediatric inflammatory bowel diseases, but clear understanding of the independent contributions of disease and nutrition is lacking. This study aimed to ascertain whether bone health could be conserved during colitis by maintaining adequate nutritional intake in growing piglets. METHODS: The effect of colitis on bone structure and strength was determined in piglets with dextran sulphate sodium-induced colitis. Piglets received either 100% macro/micronutrient requirements or 50% macro/100% micronutrient requirements. Femurs were analyzed for dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, microcomputed tomography, and 3-point bending tests. RESULTS: Colitis, regardless of a well-nourished or malnourished diet, compromised areal bone mineral density (-17%) and volumetric bone mineral density (-20%) in cortical and trabecular bone. Structural integrity at mid-diaphysis was maintained during colitis; however, lower cortical area, trabecular area, and bone mineral content resulted in lower energy to break. CONCLUSION: Colitis compromises both bone structure and strength of long bones in piglets, independent of macronutrient intakes. Although confirmation of these findings in pediatric cohorts is needed, these data identify aspects of bone health that may be affected by inflammatory bowel disease.

Experimental colitis and malnutrition differentially affect the metabolism of glutathione and related sulfhydryl metabolites in different tissues.

PURPOSE: Inflammatory bowel diseases (IBD) are characterized by severe inflammation within the gastrointestinal (GI) tract. This inflammation is known to drive the catabolism of protein in the affected tissue and modulate systemic protein metabolism. Yet despite the established increase in oxidative stress and changes in protein catabolism, little is known as to the effects of IBD on metabolism of glutathione (GSH) and related metabolites. The aim of this study was to conduct a comprehensive analysis of the response of GSH and related sulfhydryl metabolites to malnutrition and GI inflammation. We hypothesized that the inflammatory stress of colitis would decrease the concentration and the synthesis of GSH in various tissues of well-nourished piglets. Additionally, the superimposition of malnutrition on colitis would further decrease glutathione status. METHODS: Healthy, well-nourished piglets were compared to those receiving dextran sulphate sodium-induced, a macronutrient-restricted diet or both. The synthesis of GSH was determined by primed constant infusion of [(15)N,(13)C2]glycine and tandem mass spectrometry analysis. Additionally, the concentrations of GSH and related sulfhydryl metabolites were also determined by UHPLC-tandem mass spectrometry-a novel analytic technique. RESULTS: In healthy piglets, GSH synthesis was highest in the liver, along with the concentrations of both cysteine and γ-glutamylcysteine. Piglets with colitis had decreased synthesis of GSH and decreased concentrations of GSH, cysteine and γ-glutamylcysteine in the distal colon compared to healthy controls. Additionally, there was no change with superimposition of malnutrition on colitis in the distal colon. CONCLUSION: Synthesis and metabolism of GSH are uniquely regulated in each tissue. Colitis, independent of nutrition, compromises GSH status and the concentration of cysteine in the distal colon of piglets with GI inflammation. The techniques developed in this study have translational applications and can be scaled for use in clinical investigation of GI inflammation.

The anabolic effect of perioperative nutrition depends on the patient's catabolic state before surgery.

OBJECTIVE: We tested the hypothesis that the anabolic effect of hypocaloric, isonitrogenous nutrition in patients undergoing colorectal surgery depends on the patient's preoperative catabolic state. BACKGROUND: Although there is evidence to suggest that total parenteral nutrition more effectively spares protein in depleted than in nondepleted cancer patients, the influence of preoperative catabolism on the anabolic effects of hypocaloric nutrition in patients undergoing elective surgery is unknown. METHODS: Seventeen patients undergoing colorectal surgery received intravenous infusion of glucose with amino acids. Feeding was administered over 72 hours, from 24 hours before until 48 hours after surgery. Glucose provided 50% of the patient's measured resting energy expenditure. Amino acids provided 20% of the resting energy expenditure. Whole-body leucine balance (difference between the incorporation of leucine into protein = protein synthesis and endogenous leucine release = proteolysis) was determined using L-[1-(13)C]leucine kinetics before and 2 days after surgery. We analyzed the association between the postoperative increase in leucine balance and the following factors: preoperative leucine balance, protein breakdown, weight loss, oxygen consumption, circulating concentrations of glucose, free fatty acids, insulin, glucagon, cortisol, albumin, age, duration of surgery, and blood loss. RESULTS: Of 6 potentially relevant variables, 4 (weight loss, protein breakdown, albumin, and cortisol) were removed because they were not significant during the stepwise linear regression procedure. Leucine balance and age were the remaining 2 factors that remained with the final regression model: Δleucine balance = 19.1 - (0.20 × age [years]) - (0.58) × leucine balance(preOP)). CONCLUSIONS: We demonstrate a significant association between the degree of preoperative catabolism, the patient's age, and the anabolic effect of hypocaloric nutrition (ClinicalTrials.gov registration ID: NCT01414946).

Parvalbumin interneuron loss mediates repeated anesthesia-induced memory deficits in mice.

Repeated or prolonged, but not short-term, general anesthesia during the early postnatal period causes long-lasting impairments in memory formation in various species. The mechanisms underlying long-lasting impairment in cognitive function are poorly understood. Here, we show that repeated general anesthesia in postnatal mice induces preferential apoptosis and subsequent loss of parvalbumin-positive inhibitory interneurons in the hippocampus. Each parvalbumin interneuron controls the activity of multiple pyramidal excitatory neurons, thereby regulating neuronal circuits and memory consolidation. Preventing the loss of parvalbumin neurons by deleting a proapoptotic protein, mitochondrial anchored protein ligase (MAPL), selectively in parvalbumin neurons rescued anesthesia-induced deficits in pyramidal cell inhibition and hippocampus-dependent long-term memory. Conversely, partial depletion of parvalbumin neurons in neonates was sufficient to engender long-lasting memory impairment. Thus, loss of parvalbumin interneurons in postnatal mice following repeated general anesthesia critically contributes to memory deficits in adulthood.

Parenteral amino acids v. dextrose infusion: an anabolic strategy to minimise the catabolic response to surgery while maintaining normoglycaemia in diabetes mellitus type 2 patients.

Loss of body protein and hyperglycaemia represent typical features of the stress response to surgery and anaesthesia. This appears to be particularly pronounced in patients with diabetes mellitus type 2. The aim of the present study was to highlight the greater benefit of amino acids (AA) as represented by positive protein balance and maintenance of blood glucose homoeostasis compared with dextrose (DEX) in diabetic patients after colorectal surgery. A total of thirteen patients underwent a 5 h stable isotope infusion study (2 h fasted, 3 h fed with an infusion of AA (n 6) or DEX (n 7)) on the second post-operative day. Glucose and protein kinetics were assessed by using the stable isotopes l-[1-¹³C]leucine and [6,6-²H2]glucose. The transition from fasted to fed state decreased endogenous glucose production (P < 0·001) in both groups, with a more profound effect in the DEX group (P = 0·031). In contrast, total glucose production was increased by the provision of DEX while being lowered by AA (P = 0·021). Feeding decreased protein oxidation (P = 0·009) and protein synthesis in the AA group, whereas DEX infusion did not affect oxidation and even decreased protein synthesis. Therefore, only AA shifted protein balance to a positive value, while patients in the DEX group remained in a catabolic state (P < 0·001). Parenteral nutritional support with AA rather than with DEX is an effective strategy to achieve a positive protein balance while maintaining normoglycaemia in diabetic patients after colorectal surgery.

Preoperative glucose and protein metabolism: the influence of diabetes mellitus type 2 in patients with colorectal tumors.

Hypermetabolism, abnormal plasma amino acid profiles, increased gluconeogenesis, and changes in liver and muscle protein turnover are well-described undesirable effects in patients with cancer and diabetes mellitus type 2 (DM2) The aim of the present study was to analyze the specific impact and interaction of these 2 disease patterns on patients' preoperative glucose and protein metabolism. Eight nondiabetic and 8 diabetic patients devoid of cachexia underwent a stable isotope infusion study on the day before surgery for colorectal cancer or adenoma with high-grade dysplasia. Protein and glucose kinetics were assessed in a fasted state by L-[1-(13)C]leucine and [6,6(2)H(2)]glucose. In diabetic patients, glucose metabolism was found to be elevated as the plasma glucose level increased (P = 0.013) and endogenous rate of appearance of glucose tended to be higher compared to nondiabetic patients (P = 0.083). Protein metabolism was not affected by the metabolic state of the 2 groups. Resting energy expenditure was higher in diabetic patients (P = 0.028). Under postabsorptive conditions, noncachectic patients with DM2 suffering from colorectal tumors showed an elevated turnover in glucose metabolism whereas the nondiabetic counterparts failed to demonstrate any metabolic changes due solely to malignancy.

Sexually dimorphic response of mice to the Western-style diet caused by deficiency of fatty acid binding protein 6 (Fabp6).

Bile acids are natural detergents that aid in the absorption of dietary lipids. Fatty acid binding protein 6 (Fabp6) is a component of the bile acid recovery system that operates in the small intestine. The aim of this study was to determine if Fabp6 deficiency causes dietary fat malabsorption. Wild-type and Fabp6-deficient mice were fed a Western-style diet (WSD) or a reference low-fat diet (LFD) for 10 weeks. The body weight gain, bile acid excretion, fat excretion, energy metabolism, and major gut microbial phyla of the mice were assessed at the end of the controlled diet period. Fabp6-/- mice exhibited enhanced excretion of both bile acids and fat on the WSD but not on the LFD diet. Paradoxically, male Fabp6-/- mice, but not female Fabp6-/- mice, had greater adiposity despite increased fat excretion. Analysis of energy intake and of expenditure by indirect calorimetry revealed sex differences in physical activity level and respiratory quotient, but these did not account for the enhanced adiposity displayed by male Fabp6-/- mice. Analysis of stool DNA showed sex-specific changes in the abundance of major phyla of bacteria in response to Fabp6 deficiency and WSD feeding. The results obtained indicate that the malabsorption of bile acids that occurs in Fabp6-/- mice is associated with dietary fat malabsorption on the high-fat diet but not on the low-fat diet. The WSD induced a sexually dimorphic increase in adiposity displayed by Fabp6-/- mice and sexually distinct pattern of change in gut microbiota composition.

Intranasal insulin rescues repeated anesthesia-induced deficits in synaptic plasticity and memory and prevents apoptosis in neonatal mice via mTORC1.

Long-lasting cognitive impairment in juveniles undergoing repeated general anesthesia has been observed in numerous preclinical and clinical studies, yet, the underlying mechanisms remain unknown and no preventive treatment is available. We found that daily intranasal insulin administration to juvenile mice for 7 days prior to repeated isoflurane anesthesia rescues deficits in hippocampus-dependent memory and synaptic plasticity in adulthood. Moreover, intranasal insulin prevented anesthesia-induced apoptosis of hippocampal cells, which is thought to underlie cognitive impairment. Inhibition of the mechanistic target of rapamycin complex 1 (mTORC1), a major intracellular effector of insulin receptor, blocked the beneficial effects of intranasal insulin on anesthesia-induced apoptosis. Consistent with this finding, mice lacking mTORC1 downstream translational repressor 4E-BP2 showed no induction of repeated anesthesia-induced apoptosis. Our study demonstrates that intranasal insulin prevents general anesthesia-induced apoptosis of hippocampal cells, and deficits in synaptic plasticity and memory, and suggests that the rescue effect is mediated via mTORC1/4E-BP2 signaling.

Maintaining adequate nutrition, not probiotic administration, prevents growth stunting and maintains skeletal muscle protein synthesis rates in a piglet model of colitis.

Malnutrition and cytokine-induced catabolism are pervasive in children with inflammatory bowel diseases (IBD), however, the benefits of aggressive nutrition support or of probiotics on nutrient and functional deficiencies and growth remain unclear. Piglets with dextran sulfate (DS)-induced colitis consuming a 50% macronutrient restricted diet (C-MR) were compared with those receiving probiotics (C-MRP) or adequate nutrition (C-WN) and with healthy well-nourished controls (REF). C-WN versus REF had reduced growth (-34% chest circumference and -22% snout-to-rump length gain) and a tendency toward lesser weight gain, but no differences in skeletal muscle protein fractional synthesis rates (FSR) or initiation of translation via the mTOR pathway were observed. Compared with C-WN, the C-MR and C-MRP piglets had lower weight gain, growth, and skeletal muscle FSR, and lower phosphorylated p70S6K1 with higher eIF4E*4E-BP1, indicative of reduced initiation of protein translation. Finally, plasma leucine concentrations were positively correlated with weight and phosphorylated p70S6K1, whereas negatively correlated with eIF4E*4E-BP1. In conclusion, reductions in weight gain, growth, protein turnover, skeletal muscle FSR, and initiation of protein translation with moderate macronutrient restriction in colitis are not ameliorated by probiotic supplementation. However, maintaining adequate nutrient intake during colitis preserves whole body protein metabolism, but growth remains compromised.

Parenteral amino acid supplementation with high-dose insulin prevents hypoaminoacidemia during cardiac surgery.

OBJECTIVES: Surgery triggers a stress response that produces insulin resistance and hyperglycemia. During cardiac surgery, the administration of high-dose insulin along with dextrose titration maintains normoglycemia, but dramatically decreases plasma amino acids (AAs) compared with preoperative fasting levels. Hypoaminoacidemia limits protein synthesis and prevents anabolic responses after surgery. We investigated whether parenteral infusion of AAs during and immediately after cardiac surgery would prevent hypoaminoacidemia in patients who receive high-dose insulin therapy. METHODS: Sixteen patients undergoing coronary artery bypass grafting surgery were randomly allocated to receive AAs with % kcal equivalent to either 20% (n = 8) or 35% (n = 8) of their measured resting energy expenditure (REE). Insulin was infused at a constant rate of 5 mU/(kg × min), whereas dextrose was titrated to maintain normoglycemia during and until 5 h after surgery. Plasma AA concentrations were measured at baseline before and after surgery. RESULTS: Compared with the 20% AA group after surgery, AA concentrations were significantly higher in the 35% AA group for 12 of 20 AAs (P < 0.032), including all branched-chain AAs. In the 20% AA group, total essential AAs decreased by 21% and nonessential AAs decreased by 14% after surgery compared with preoperative fasting levels. In contrast, giving 35% AAs prevented this unfavorable decrease in AAs, and in fact allowed for a 23% and 12% increase in essential and nonessential AAs, respectively. CONCLUSIONS: AA supplementation at 35% REE, but not 20% REE, can effectively prevent hypoaminoacidemia caused by high-dose insulin therapy during cardiac surgery.

Association between pre-breeding metabolic profiles and reproductive performance in heifers and lactating dairy cows.

Lactating cows and nulliparous heifers are in distinctive and unique physiological conditions when they are approaching the planned time of breeding, at approximately 60 days in milk and 13-15 months of age, respectively. This study aimed to profile the metabolic milieu in heifers (N = 14) and lactating cows (N = 15) in the weeks leading up to planned time of breeding. All cows were followed for a period of 15 weeks, from 3 weeks pre-calving to 12 weeks post-calving, while heifers were monitored for a period of 4 weeks leading up to the tentative week of breeding (pre-breeding period). For data analysis, we further divided cows into primiparous (N = 8) and multiparous (N = 7) cows owing to the significant difference in their milk yield. Assessment of reproductive performance showed that primiparous and multiparous cows tended to have lower pregnancy rates compared to heifers (P < 0.1). Plasma concentrations of ß-hydroxybutyric acid were about 2-fold higher in multiparous cows than those of heifers in the week leading up to planned time of breeding (P < 0.05). Total bile acid levels during the pre-breeding period were higher in all lactating cows compared to heifers (P < 0.05) and glucose levels were lower in lactating cows (P < 0.05). Triglyceride concentrations were lowest in multiparous cows compared to both primiparous cows and nulliparous heifers (P < 0.05). In addition, lactating cows had higher concentrations of total-cholesterol and the high-density lipoprotein and low-density lipoprotein compared to heifers (P < 0.05). Conversely, concentrations of very low-density lipoprotein were lower in multiparous cows than primiparous cows and nulliparous heifers (P < 0.05). There were no differences in plasma glutathione levels, as measured by liquid chromatography-tandem mass spectrometry, between the groups, but the ferric reducing ability of plasma was higher in lactating cows compared to heifers (P < 0.05). These data establish the differences in the profile of metabolic and oxidative markers during the period approaching planned time of breeding in lactating cows compared to nulliparous heifers. As certain metabolites in the plasma have been shown to be represented in the ovarian follicular microenvironment, the unique profiles may influence reproductive performance in dairy cattle in different physiological stages.

Anticatabolic effects of avoiding preoperative fasting by intravenous hypocaloric nutrition: a randomized clinical trial.

OBJECTIVE: We tested the hypothesis that the avoidance of preoperative fasting by hypocaloric nutrition attenuates protein catabolism after surgery. SUMMARY BACKGROUND DATA: Prolonged fasting before major abdominal procedures has been demonstrated to accentuate the catabolic response to surgery. METHODS: Twenty-two patients undergoing colorectal cancer surgery were randomly assigned to receive glucose and amino acids intravenously starting either 20 hours before the operation or with surgical skin incision. Nutrition was administered until the second postoperative day, with glucose providing 50% and amino acids 20% of each patient's measured resting energy expenditure. Whole body leucine and glucose kinetics were assessed by L-[1-(13)C]leucine and [6,6-(2)H(2)]glucose before and after surgery. Fractional synthesis rates of muscle protein, albumin, and fibrinogen were determined using primed continuous infusions of L-[(2)H(5)]phenylalanine postoperatively, whereas the expression of mRNA of proteolytic genes in muscle (Mafbx/atrogin-1, ubiquitin, Murf 1) was determined by quantitative RT-PCR. Circulating concentrations of glucose, lactate, amino acids, insulin, glucagon, and cortisol were also measured. This study has been registered at ClinicalTrials.gov (Identifier: NCT00614133). RESULTS: Preoperative feeding inhibited endogenous protein breakdown (fasting group: 128 +/- 23 micromol . kg(-1) . h(-1); nutrition group: 96 +/- 22 micromol . kg(-1) . h(-1); P = 0.02) and blunted the increase in amino acid oxidation (fasting group: 27 +/- 5 micromol . kg(-1) . h(-1); nutrition group: 20 +/- 5 micromol . kg(-1) . h(-1); P = 0.03), resulting in positive whole-body protein balance after surgery (fasting group: -10 +/- 4 micromol . kg(-1) . h(-1); nutrition group: 1 +/- 3 micromol . kg(-1) . h(-1); P < 0.001). This anabolic response was associated with decreased muscle proteolytic gene expression and increased hepatic albumin synthesis. Total plasma protein, fibrinogen, and muscle protein synthesis were not affected. CONCLUSIONS: Hypocaloric nutrition decreases protein catabolism, with a contribution from the ubiquitin pathway in muscle, and stimulates albumin synthesis after colorectal surgery if initiated 1 day before the operation.

Probiotics stimulate liver and plasma protein synthesis in piglets with dextran sulfate-induced colitis and macronutrient restriction.

Adequate nutrition and probiotics have each been shown to reduce the severity of colitis, but their impact on hepatic and gastrointestinal protein metabolism has not been studied. Our objective was to determine whether maintaining adequate nutrition compared with administering probiotics affected protein synthesis, colon histopathology, and oxidative stress in our macronutrient-restricted piglet model of colitis. Piglets (n = 8/group) receiving dextran sulfate to induce colitis were randomized to 3 treatment groups: macronutrient restricted (MR); macronutrient restricted with VSL #3 probiotics (MRP), or well nourished (WNC). An additional 8 piglets served as healthy references for comparative purposes given the unique nature of the experimental model. A primed, constant infusion of the tracer L-[ring-(2)H(5)]phenylalanine was performed in colitis piglets after 14 d to determine the fractional synthesis rates of proteins in small intestinal mucosa, colon, and liver and of plasma proteins (total protein, fibrinogen, albumin). Colon histopathology and oxidative stress were also assessed. Compared with MR piglets, both WNC and MRP piglets had higher protein synthesis rates in liver and plasma protein pools. However, only adequate nutrition increased protein synthesis in the colon and decreased colitis severity. Whereas probiotics did not stimulate gastrointestinal protein synthesis or reduce colitis severity, a still-unidentified signaling mechanism between the gut and liver seems to be responsible for the probiotic-induced increase in liver protein and plasma protein synthesis. These data underscore the importance of maintaining nutrient intake in pediatric patients with gastrointestinal disease. A strategy for correcting compromised nutrition seems to be more beneficial for reducing damage during colitis than using probiotics only.