Statin treatment reduces leucine turnover, but does not affect endogenous production of beta-hydroxy-beta-methylbutyrate (HMB).

BACKGROUND: Statins, or hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, are one of the most commonly prescribed medications for lowering cholesterol. Myopathic side-effects ranging from pain and soreness to critical rhabdomyolysis are commonly reported and often lead to discontinuation. The pathophysiological mechanism is, in general, ascribed to a downstream reduction of Coenzyme Q10 synthesis. HMG-CoA is a metabolite of leucine and its corresponding keto acid α-ketoisocaproic acid (KIC) and ß-hydroxy-ß-methylbutyrate (HMB), however, little is known about the changes in the metabolism of leucine and its metabolites in response to statins. OBJECTIVE: We aimed to investigate if statin treatment has implications on the upstream metabolism of leucine to KIC and HMB, as well as on other branched chain amino acids (BCAA). DESIGN: 12 hyperlipidemic older adults under statin treatment were recruited. The study was conducted as a paired prospective study. Included participants discontinued their statin treatment for 4 weeks before they returned for baseline measurements (before). Statin treatment was then reintroduced, and the participants returned for a second study day 7 days after reintroduction (after statin). On study days, participants were injected with stable isotope pulses for measurement of the whole-body production (WBP) of all BCAA (leucine, isoleucine and valine), along with their respective keto acids and HMB. RESULTS: We found a reduced leucine WBP (22 %, p = 0.0033), along with a reduction in valine WBP (13 %, p = 0.0224). All other WBP of BCAA and keto acids were unchanged. There were no changes in the WBP of HMB. CONCLUSIONS: Our study shows that statin inhibition of HMG-CoA reductase has an upstream impact on the turnover of leucine and valine. Whether this impairment in WBP of leucine may contribute to the known pathophysiological side effects of statins on muscle remains to be further investigated.

Postprandial concentration of circulating branched chain amino acids are able to predict the carbohydrate content of the ingested mixed meal.

BACKGROUND: The amount of the macronutrients protein and carbohydrate (CHO) in a mixed meal is known to affect each other's digestion, absorption, and subsequent metabolism. While the effect of the amount of dietary protein and fat on the glycemic response is well studied, the ability of postprandial plasma amino acid patterns to predict the meal composition is unknown. OBJECTIVE: To study the postprandial plasma amino acid patterns in relation to the protein, CHO, and fat content of different mixed meals and to investigate if these patterns can predict the macronutrient meal composition. DESIGN: Ten older adults were given 9 meals with 3 different levels (low, medium, and high) of protein, CHO, and fat in different combinations, taking the medium content as that of a standardized western meal. We monitored the postprandial plasma response for amino acids, glucose, insulin, and triglycerides for 8 h and the areas under the curve (AUC) were subsequently calculated. Multiple regression analysis was performed to determine if amino acid patterns could predict the meal composition. RESULTS: Increasing meal CHO content reduced the postprandial plasma response of several amino acids including all branched chain amino acids (BCAA) (leucine; q < 0.0001, isoleucine; q = 0.0035, valine; q = 0.0022). The plasma BCAA patterns after the meal significantly predicted the meal's CHO content (leucine; p < 0.0001, isoleucine; p = 0.0003, valine; p = 0.0008) along with aspartate (p < 0.0001), tyrosine (p < 0.0001), methionine (p = 0.0159) and phenylalanine (p = 0.0332). Plasma citrulline predicted best the fat content of the meal (p = 0.0024). CONCLUSIONS: The postprandial plasma BCAA patterns are lower with increasing meal CHO content and are strong predictors of a mixed meal protein and CHO composition, as are plasma citrulline for the fat content. We hypothesize that postprandial plasma amino acid concentrations can be used to predict the meal's macronutrient composition.

The money behind academic publishing. / Pengene bak vitenskapelig publisering.

The academic publishing industry earns high profits and shapes how we undertake medical research. With the increasing demand for free access to articles, academic publishing is now changing, but is it changing for the better?

Nutritional support for critically ill patients in the intensive care unit. / Ernæring hos kritisk syke intensivpasienter.

Patients in intensive care have increased nutritional needs but are often incapable of eating independently. When should intravenous parenteral nutrition be started, and what is the optimal dose? Here we review the recently updated European guidelines on nutritional support in intensive care patients.

Perioperative Infusion of Glucagon-Like Peptide-1 Prevents Insulin Resistance After Surgical Trauma in Female Pigs.

Insulin resistance is an independent negative predictor of outcome after elective surgery and increases mortality among surgical patients in intensive care. The incretin hormone glucagon-like peptide-1 (GLP-1) potentiates glucose-induced insulin release from the pancreas but may also increase insulin sensitivity in skeletal muscle and directly suppress hepatic glucose release. Here, we investigated whether a perioperative infusion of GLP-1 could counteract the development of insulin resistance after surgery. Pigs were randomly assigned to three groups; surgery/control, surgery/GLP-1, and sham/GLP-1. Both surgery groups underwent major abdominal surgery. Whole-body glucose disposal (WGD) and endogenous glucose release (EGR) were assessed preoperatively and postoperatively using D-[6,6-2H2]-glucose infusion in combination with hyperinsulinemic euglycemic step-clamping. In the surgery/control group, peripheral insulin sensitivity (i.e., WGD) was reduced by 44% relative to preoperative conditions, whereas the corresponding decline was only 9% for surgery/GLP-1 (P < 0.05). Hepatic insulin sensitivity (i.e., EGR) remained unchanged in the surgery/control group but was enhanced after GLP-1 infusion in both surgery and sham animals (40% and 104%, respectively, both P < 0.05). Intraoperative plasma glucose increased in surgery/control (∼20%) but remained unchanged in both groups receiving GLP-1 (P < 0.05). GLP-1 diminished an increase in postoperative glucagon levels but did not affect skeletal muscle glycogen or insulin signaling proteins after surgery. We show that GLP-1 improves intraoperative glycemic control, diminishes peripheral insulin resistance after surgery, and suppresses EGR. This study supports the use of GLP-1 to prevent development of postoperative insulin resistance.

Skeletal muscle mitochondria exhibit decreased pyruvate oxidation capacity and increased ROS emission during surgery-induced acute insulin resistance.

Development of acute insulin resistance represents a negative factor after surgery, but the underlying mechanisms are not fully understood. We investigated the postoperative changes in insulin sensitivity, mitochondrial function, enzyme activities, and release of reactive oxygen species (ROS) in skeletal muscle and liver in pigs on the 2nd postoperative day after major abdominal surgery. Peripheral and hepatic insulin sensitivity were assessed by D-[6,6-²H2]glucose infusion and hyperinsulinemic euglycemic step clamping. Surgical trauma elicited a decline in peripheral insulin sensitivity (∼34%, P<0.01), whereas hepatic insulin sensitivity remained unchanged. Intramyofibrillar (IFM) and subsarcolemma mitochondria (SSM) isolated from skeletal muscle showed a postoperative decline in ADP-stimulated respiration (V(ADP)) for pyruvate (∼61%, P<0.05, and ∼40%, P<0.001, respectively), whereas V(ADP) for glutamate and palmitoyl-L-carnitine (PC) was unchanged. Mitochondrial leak respiration with PC was increased in SSM (1.9-fold, P<0.05) and IFM (2.5-fold, P<0.05), indicating FFA-induced uncoupling. The activity of the pyruvate dehydrogenase complex (PDC) was reduced (∼32%, P<0.01) and positively correlated to the decline in peripheral insulin sensitivity (r=0.748, P<0.05). All other mitochondrial enzyme activities were unchanged. No changes in mitochondrial function in liver were observed. Mitochondrial H2O2 and O2·â» emission was measured spectrofluorometrically, and H2O2 was increased in SSM, IFM, and liver mitochondria (∼2.3-, ∼2.5-, and ∼2.3-fold, respectively, all P<0.05). We conclude that an impairment in skeletal muscle mitochondrial PDC activity and pyruvate oxidation capacity arises in the postoperative phase along with increased ROS emission, suggesting a link between mitochondrial function and development of acute postoperative insulin resistance.

Preoperative carbohydrate supplementation attenuates post-surgery insulin resistance via reduced inflammatory inhibition of the insulin-mediated restraint on muscle pyruvate dehydrogenase kinase 4 expression.

BACKGROUND & AIMS: We hypothesized that the so far poorly understood improvement in postoperative insulin sensitivity, when surgery is preceded by a carbohydrate (CHO) drink, occurs via attenuation of skeletal muscle inflammatory responses to surgery, improved insulin signaling and attenuated expression of muscle pyruvate dehydrogenase kinase (PDK) 4. METHODS: Vastus lateralis muscle biopsies, collected before and after major abdominal surgery and during postoperative hyperinsulinaemic-euglycaemic clamping from 16 pigs randomized to either 200 ml of a CHO-supplemented drink 2 h before surgery (CHO, 25 g; n = 8), or preoperative overnight fasting (fasted; n = 8), were analyzed by fast qRT-PCR and IR-Western blotting. RESULTS: During clamping, expression of IKKß, SOCS3 and the ratio of phosphorylated/total JNK2 proteins were lower in the CHO group than in the fasted group (-1.0 vs. 2.9-fold, P < 0.001; -0.6 vs. 3.2-fold, P < 0.01; and -0.5 vs. 1.1-fold, P < 0.02, respectively). Furthermore, the ratio of Ser(307)-phosphorylated (inhibition)/total IRS1 protein was reduced only in the CHO group (-2.4 fold, P < 0.02), whereas FOXO1 phosphorylation (inactivation), which correlated negatively with PDK4 mRNA (r(2) = 0.275, P < 0.05), was lower in the CHO group than in the fasted group (-1.1-fold, P > 0.05 vs. -2.3-fold, P = 0.05). Post-surgery, PDK4 mRNA increased ∼20-fold (P < 0.01) in both groups, but was reversed to a greater extent by insulin in the CHO group (-40.5 vs. -22.7-fold, P < 0.05), resulting in 5-fold lower PDK4 protein levels, which correlated negatively with insulin-stimulated whole-body glucose disposal rates (r(2) = -0.265, P < 0.05). CONCLUSIONS: Preoperative carbohydrate supplementation was found to ameliorate postoperative insulin sensitivity by reducing muscle inflammatory responses and improved insulin inhibition of FOXO1-mediated PDK4 mRNA and protein expression after surgery.

Single-dose carbohydrate treatment in the immediate preoperative phase diminishes development of postoperative peripheral insulin resistance.

BACKGROUND & AIMS: Preoperative oral carbohydrate (CHO) treatment is known to reduce postoperative insulin resistance, but the necessity of a preoperative evening dose is uncertain. We investigated the effect of single-dose CHO treatment two hours before surgery on postoperative insulin sensitivity. METHODS: Thirty two pigs (∼ 30 kg) were randomized to 4 groups (n = 8) followed by D-[6,6-(2)H2] glucose infusion and hyperinsulinemic-euglycemic step clamping. Two groups received a morning drink of 25 g carbohydrate (CHO/surgery and CHO/control). Animals in the other two groups were fasted overnight (fasting/surgery and fasting/control). Counter-regulatory hormones, free fatty acids (FFA) and liver and muscle glycogen content were measured serially. RESULTS: Glucose infusion rates needed to maintain euglycemia were higher after CHO/surgery than fasting/surgery during low (8.54 ± 0.82 vs. 6.15 ± 0.27 mg/kg/min, P < 0.05), medium (17.26 ± 1.08 vs. 14.02 ± 0.56 mg/kg/min, P < 0.02) and high insulin clamping (19.83 ± 0.95 vs. 17.16 ± 0.58 mg/kg/min, P < 0.05). The control groups exhibited identical insulin sensitivity. Compared to their respective controls, insulin-stimulated whole-body glucose disposal was significantly reduced after fasting/surgery (-41%, P < 0.001), but not after CHO/surgery (-16%, P = 0.180). CHO reduced FFA perioperatively (P < 0.05) and during the clamp procedures (P < 0.02), but did not affect hepatic insulin sensitivity, liver and muscle glycogen content or counter-regulatory hormone profiles. A strong negative correlation between peripheral insulin sensitivity and mean cortisol levels was seen in fasted (R = -0.692, P = 0.003), but not in CHO loaded pigs. CONCLUSIONS: Single-dose preoperative CHO treatment is sufficient to reduce postoperative insulin resistance, possibly due to the antilipolytic effects and antagonist properties of preoperative hyperinsulinemia on the suppressant actions of cortisol on carbohydrate oxidation.

The acute phase of experimental cardiogenic shock is counteracted by microcirculatory and mitochondrial adaptations.

The mechanisms contributing to multiorgan dysfunction during cardiogenic shock are poorly understood. Our goal was to characterize the microcirculatory and mitochondrial responses following ≥ 10 hours of severe left ventricular failure and cardiogenic shock. We employed a closed-chest porcine model of cardiogenic shock induced by left coronary microembolization (n = 12) and a time-matched control group (n = 6). Hemodynamics and metabolism were measured hourly by intravascular pressure catheters, thermodilution, arterial and organ specific blood gases. Echocardiography and assessment of the sublingual microcirculation by sidestream darkfield imaging were performed at baseline, 2 ± 1 and 13 ± 3 (mean ± SD) hours after coronary microembolization. Upon hemodynamic decompensation, cardiac, renal and hepatic mitochondria were isolated and evaluated by high-resolution respirometry. Low cardiac output, hypotension, oliguria and severe reductions in mixed-venous and hepatic O2 saturations were evident in cardiogenic shock. The sublingual total and perfused vessel densities were fully preserved throughout the experiments. Cardiac mitochondrial respiration was unaltered, whereas state 2, 3 and 4 respiration of renal and hepatic mitochondria were increased in cardiogenic shock. Mitochondrial viability (RCR; state 3/state 4) and efficiency (ADP/O ratio) were unaffected. Our study demonstrates that the microcirculation is preserved in a porcine model of untreated cardiogenic shock despite vital organ hypoperfusion. Renal and hepatic mitochondrial respiration is upregulated, possibly through demand-related adaptations, and the endogenous shock response is thus compensatory and protective, even after several hours of global hypoperfusion.

The Accu-Chek Mobile blood glucose monitoring system used under controlled conditions meets ISO 15197 standards in the hands of diabetes patients.

BACKGROUND: Self-monitoring of blood glucose is a cornerstone of diabetes management. The aim of this study was to evaluate the analytical quality and the ease of use of the Accu-Chek Mobile, a new glucose monitoring system designed for capillary blood testing by diabetic patients. MATERIALS AND METHODS: The performance of the Accu-Chek Mobile was evaluated both in the hands of a scientist and of diabetes patients. The designated comparative method was a hexokinase-based laboratory method (Architect ci8200). Diabetics (N = 88) with previous experience of self-testing were recruited for the study. Patient samples, containing glucose in concentrations mainly between ˜4 and ˜20 mmol/L, were analyzed in duplicates both on the Accu-Chek Mobile and with the comparative method. The patients answered a questionnaire about the ease of use of the meter. RESULTS: The meter yields reproducible readings, with an imprecision CV <5% as required by the American Diabetes Association (ADA). Of the glucose concentrations obtained by both the scientist and the patients, more than 95% of the individual results were within ± 20% of the comparative method, meeting the ISO 15197 accuracy goal, but not the stricter ± 10% ADA goal. CONCLUSION: Accu-Chek Mobile is a user-friendly glucometer that in a normo- and hyperglycemic range fulfils the ISO 15197 accuracy requirement, also in the hands of diabetes patients.

Cardioprotective effect of the PPAR ligand tetradecylthioacetic acid in type 2 diabetic mice.

Tetradecylthioacetic acid (TTA) is a novel peroxisome proliferator-activated receptor (PPAR) ligand with marked hypolipidemic and insulin-sensitizing effects in obese models. TTA has recently been shown to attenuate dyslipidemia in patients with type 2 diabetes, corroborating the potential for TTA in antidiabetic therapy. In a recent study on normal mice, we showed that TTA increased myocardial fatty acid (FA) oxidation, which was associated with decreased cardiac efficiency and impaired postischemic functional recovery. The aim of the present study was, therefore, to elucidate the effects of TTA treatment (0.5%, 8 days) on cardiac metabolism and function in a hyperlipidemic type 2 diabetic model. We found that TTA treatment increased myocardial FA oxidation, not only in nondiabetic (db/+) mice but also in diabetic (db/db) mice, despite a clear lipid-lowering effect. Although TTA had deleterious effects in hearts from nondiabetic mice (decreased efficiency and impaired mitochondrial respiratory capacity), these effects were not observed in db/db hearts. In db/db hearts, TTA improved ischemic tolerance, an effect that is most likely related to the antioxidant property of TTA. The present study strongly advocates the need for investigation of the cardiac effects of PPAR ligands used in antidiabetic/hypolipidemic therapy, because of their pleiotropic properties.

Hyperinsulinemic euglycemic step clamping with tracer glucose infusion and labeled glucose infusate for assessment of acute insulin resistance in pigs.

The present study aimed to establish hyperinsulinemic euglycemic step clamping with tracer glucose infusion and labeled glucose infusate (step hot-GINF HEC) for assessment of acute insulin resistance in anesthetized pigs and to arrange for combination with invasive investigative methods. Tracer enrichment was measured during D-[6,6-(2)H(2)]glucose infusion before and after surgical instrumentation (n = 8). Insulin dose-response characteristics were determined by two step hot-GINF HEC procedures, with accordingly labeled glucose infusates performed at a total of six insulin infusion rates ranging from 0.2 to 2.0 mU kg(-1) min(-1) (n = 8). Finally, three-step hot-GINF HEC (0.4, 1.2, and 2.0 mU kg(-1) min(-1)) was performed subsequent to major surgical trauma (n = 8). Tracer enrichment, basal glucose kinetics, and circulating levels of C-peptide, cortisol, glucagon, and catecholamines were not influenced by surgical instrumentation. Mean intraindividual coefficient of variance levels for glucose infusion rates and repeatedly measured insulin, glucose, and tracer enrichment indicated stable clamping conditions. Basal and maximal insulin-stimulated glucose utilization was twice as high as in humans at approximately 5.5 and 21 mg kg(-1) min(-1). Surgical trauma elicited pronounced peripheral and moderate hepatic insulin unresponsiveness (45% lower whole body glucose disposal and 19% less suppressed endogenous glucose release) and apparently diminished metabolic insulin clearance. Step hot-GINF HEC seems suitable for assessment of acute insulin resistance in anesthetized pigs, and combination with invasive investigative methods requiring surgical instrumentation can be accomplished without the premises for utilization of the technique being altered, but attention must be paid to alterations in metabolic insulin clearance.

Cardiac peroxisome proliferator-activated receptor-alpha activation causes increased fatty acid oxidation, reducing efficiency and post-ischaemic functional loss.

AIMS: Myocardial fatty acid (FA) oxidation is regulated acutely by the FA supply and chronically at the transcriptional level owing to FA activation of peroxisome proliferator-activated receptor-alpha (PPARalpha). However, in vivo administration of PPARalpha ligands has not been shown to increase cardiac FA oxidation. In this study we have examined the cardiac response to in vivo administration of tetradecylthioacetic acid (TTA, 0.5% w/w added to the diet for 8 days), a PPAR agonist with primarily PPARalpha activity. METHODS AND RESULTS: Despite the fact that TTA treatment decreased plasma concentrations of lipids [FA and triacylglycerols (TG)], hearts from TTA-treated mice showed increased mRNA expression of PPARalpha target genes. Cardiac substrate utilization, ventricular function, cardiac efficiency, and susceptibility to ischaemia-reperfusion were examined in isolated perfused hearts. In accordance with the mRNA changes, myocardial FA oxidation was increased 2.5-fold with a concomitant reduction in glucose oxidation. This increase in FA oxidation was abolished in PPARalpha-null mice. Thus, it appears that the metabolic effects of TTA on the heart must be owing to a direct stimulatory effect on cardiac PPARalpha. Hearts from TTA-treated mice also showed a marked reduction in cardiac efficiency (because of a two-fold increase in unloaded myocardial oxygen consumption) and decreased recovery of ventricular contractile function following low-flow ischaemia. CONCLUSION: This study for the first time observed that in vivo administration of a synthetic PPARalpha ligand elevated FA oxidation, an effect that was also associated with decreased cardiac efficiency and reduced post-ischaemic functional recovery.