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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. [ABSTRACT FROM AUTHOR]

Background: Surgical injury provokes a stress response that is thought to be pronounced in patients with diabetes mellitus type 2 (DM2) leading to intensified catabolism. The aim of this study was to compare the effects of perioperative epidural analgesia (EDA) versus patient controlled analgesia (PCA) and amino acid infusion on postoperative metabolism in patients with and without DM2.Methods: For this study, 12 nondiabetic patients and 12 diabetic patients undergoing colorectal surgery were randomly assigned to 4 groups (n = 6 per group) receiving either EDA (nondiabetic EDA and diabetic EDA [DEDA group]) or PCA with morphine (nondiabetic PCA and diabetic PCA) for perioperative pain control. Protein and glucose kinetics were measured on the second postoperative day using L-[1-13C]leucine and [6,6-2H2]glucose infusion during a fasted state and a 3-hr fed state with amino acid infusion.Results: The transition from the fasted to fed state suppressed endogenous rate of appearance (Ra) of glucose (P G 0.001) with a distinct effect for the DEDA group (P G 0.001). The Ra of leucine and the endogenous rate of appearance of leucine tended to be lower in the DEDA group(P = 0.056 and P = 0.07). Leucine oxidation was more suppressed in the DEDA group (P = 0.02) and when receiving amino acids(P = 0.001). Diabetic patients achieved a higher protein balance than nondiabetic patients (P = 0.032) and when receiving EDA instead of PCA (P = 0.012) or infusion of amino acids (P = 0.014).Conclusions: A short-term infusion of amino acids reduced protein breakdown, increased protein synthesis, and rendered protein balance positive. This anabolic effect was pronounced in diabetic patients with EDA compared with nondiabetic patients or PCA, respectively, and prevented an undesirable hyperglycemia. [ABSTRACT FROM AUTHOR]

The changes in protein metabolism of severe childhood malnutrition are generally perceived as a metabolic adaptation to chronic protein undernutrition. However, severe malnutrition is invariably accompanied by infections which also have profound effects on protein metabolism. This study aimed to distinguish the effect of protein undernutrition from that of an inflammatory stimulus on muscle and plasma protein synthesis rates. Two groups of five piglets consumed diets containing either 23% or 3% protein for 4 wk. They then were infused intravenously with 2H3-leucine before and 48 h after subcutaneous injections of turpentine to measure the fractional synthesis rates (FSR) of muscle protein and both the FSR and the absolute synthesis rates (ASR) of albumin and fibrinogen. Prior to turpentine injection, compared to control piglets, protein-deficient piglets had significantly lower muscle FSR and plasma concentrations of both albumin and fibrinogen, although only albumin had lower FSR and ASR. Turpentine injection decreased muscle FSR but increased the FSR, ASR and plasma concentrations of both albumin and fibrinogen in control piglets. In protein-deficient piglets, the inflammatory stress caused a further decrease in muscle protein FSR and in plasma albumin concentration despite marked increases in albumin FSR and ASR. Fibrinogen FSR, ASR and plasma concentration were increased. We conclude that protein undernutrition and inflammation elicit the same kinetic response in muscle protein but different kinetic responses in plasma proteins. Furthermore, whereas protein deficiency reduces the plasma albumin pool via a reduction in albumin synthesis, inflammation reduces it through a stimulation of catabolism and/or loss from the intravascular space. [ABSTRACT FROM AUTHOR]

The use of plasma protein concentrations to assess protein-nutritional status has been questioned because concentrations and kinetics are affected by factors other than protein intake. To determine the effect of protein deficiency on plasma protein concentration and synthesis, two groups of four piglets consumed diets containing either 20 or 3% protein. After 8 wk, 2H3-leucine was infused intravenously to measure the fractional and absolute synthesis rates (FSR and ASR) of albumin, transferrin, retinol binding protein (RBP), transthyretin (TTR), a new peptide called TTR2, the high density apolipoprotein (HDL-apoA-1), fibrinogen, and haptoglobin. Compared with controls, protein-deficient pigs had significantly lower (P < 0.05) plasma albumin, RBP and TTR2 concentrations, significantly slower (P < 0.05) FSR of fibrinogen, HDL-apoA-1, transferring and TTR2, significantly lower (P < 0.05) ASR of albumin, fibrinogen, transferrin, and TTR2, and a significantly higher (P < 0.05) ASR of TTR. Fibrinogen and transferrin concentrations did not differ between groups, but transthyretin concentration was higher in protein-deficient pigs. These results suggest that protein-nutritional status cannot be predicted from the concentrations of all plasma proteins, that chronic protein deficiency affects the rate of synthesis of only some plasma proteins, and that the kinetic response of plasma proteins to protein restriction cannot be predicted from measurements of plasma concentrations. [ABSTRACT FROM AUTHOR]

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.

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- 2 H 5 ]phenylalanine was used to measure absolute synthesis rates (ASR) of albumin and fibrinogen. A priming dose of L-[ring- 2 H 5 ]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)., (© 2021. The Author(s).)

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., (© 2021. The Author(s).)

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.

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., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

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., (© 2020 Wiley Periodicals, Inc.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

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 β-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., (Copyright © 2019. Published by Elsevier Inc.)