Van Den Berghe Research Articles

The Antioxidant Transcription Factor Nrf2 Negatively Regulates Autophagy and Growth Arrest Induced by the Anticancer Redox Agent Mitoquinone

Mitoquinone (MitoQ) is a synthetically modified, redox-active ubiquinone compound that accumulates predominantly in mitochondria. We found that MitoQ is 30-fold more cytotoxic to breast cancer cells than to healthy mammary cells. MitoQ treatment led to irreversible inhibition of clonogenic growth of breast cancer cells through a combination of autophagy and apoptotic cell death mechanisms. Relatively limited cytotoxicity was seen with the parent ubiquinone coenzyme Q(10.) Inhibition of cancer cell growth by MitoQ was associated with G(1)/S cell cycle arrest and phosphorylation of the checkpoint kinases Chk1 and Chk2. The possible role of oxidative stress in MitoQ activity was investigated by measuring the products of hydroethidine oxidation. Increases in ethidium and dihydroethidium levels, markers of one-electron oxidation of hydroethidine, were observed at cytotoxic concentrations of MitoQ. Keap1, an oxidative stress sensor protein that regulates the antioxidant transcription factor Nrf2, underwent oxidation, degradation, and dissociation from Nrf2 in MitoQ-treated cells. Nrf2 protein levels, nuclear localization, and transcriptional activity also increased following MitoQ treatment. Knockdown of Nrf2 caused a 2-fold increase in autophagy and an increase in G(1) cell cycle arrest in response to MitoQ but had no apparent effect on apoptosis. The Nrf2-regulated enzyme NQO1 is partly responsible for controlling the level of autophagy. Keap1 and Nrf2 act as redox sensors for oxidative perturbations that lead to autophagy. MitoQ and similar compounds should be further evaluated for novel anticancer activity.

Increased Glucocorticoid Receptor Expression and Activity Mediate the LPS Resistance of SPRET/EI Mice

SPRET/Ei mice are extremely resistant to acute LPS-induced lethal inflammation when compared with C57BL/6. We found that in vivo SPRET/Ei mice exhibit strongly reduced expression levels of cytokines and chemokines. To investigate the role of the potent anti-inflammatory glucocorticoid receptor (GR) in the SPRET/Ei phenotype, mice were treated with the GR antagonist RU486 or bilateral adrenalectomy. Under such conditions, both C57BL/6 and SPRET/Ei mice were strongly sensitized to LPS, and the differences in LPS response between SPRET/Ei and C57BL/6 mice were completely gone. These results underscore the central role of GR in the LPS hyporesponsiveness of SPRET/Ei mice. Compared with C57BL/6, SPRET/Ei mice were found to express higher GR levels, which were reflected in increased GR transactivation. Using a backcross mapping strategy, we demonstrate that the high GR transcription levels are linked to the Nr3c1 (GR) locus on chromosome 18 itself. Unexpectedly, SPRET/Ei mice exhibit a basal overactivation of the hypothalamic-pituitary-adrenal axis, namely strongly increased corticosterone levels, ACTH levels, and adrenocortical size. As a consequence of the excess of circulating glucocorticoids (GCs), levels of hepatic gluconeogenic enzymes are increased, and insulin secretion from pancreatic β-cells is impaired, both of which result in hyperglycemia and glucose intolerance in SPRET/Ei mice. We conclude that SPRET/Ei mice are unique as they display an unusual combination of elevated GR expression and increased endogenous GC levels. Hence, these mice provide a new and powerful tool for the study of GR- and GC-mediated mechanisms, including immune repressive functions, neuroendocrine regulation, insulin secretion, and carbohydrate metabolism.

Journal of Diabetes News

<i>Journal of Diabetes</i> News

Symplectic exponentially-fitted four-stage Runge–Kutta methods of the Gauss type

The construction of symmetric and symplectic exponentially-fitted Runge---Kutta methods for the numerical integration of Hamiltonian systems with oscillatory solutions deserves a lot of interest. In previous papers fourth-order and sixth-order symplectic exponentially-fitted integrators of Gauss type, either with fixed or variable nodes, have been derived. In this paper new such integrators of eighth-order are studied and constructed by making use of the six-step procedure of Ixaru and Vanden Berghe (2004). Numerical experiments for some oscillatory problems are presented.

Loss of Cystic Fibrosis Transmembrane Conductance Regulator Function Enhances Activation of p38 and ERK MAPKs, Increasing Interleukin-6 Synthesis in Airway Epithelial Cells Exposed to Pseudomonas aeruginosa

In cystic fibrosis (CF), the absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) translates into chronic bacterial infection, excessive inflammation, tissue damage, impaired lung function and eventual death. Understanding the mechanisms underlying this vicious circle of inflammation is important to design better therapies for CF. We found in CF lung biopsies increased immunoreactivity for p38 MAPK activity markers. Moreover, when compared with their non-CF counterpart, airway epithelial cells expressing the most common mutation in CF (CFTRDeltaF508) were more potent at inducing neutrophil chemotaxis through increased interleukin (IL)-6 synthesis when challenged with Pseudomonas aeruginosa diffusible material. We then discovered that in CFTRDeltaF508 cells, the p38 and ERK MAPKs are hyperactivated in response to P. aeruginosa diffusible material, leading to increased IL-6 mRNA expression and stability. Moreover, although TLR5 contributes to p38 MAPK activation upon P. aeruginosa challenge, it only played a weak role in IL-6 synthesis. Instead, we found that the production of reactive oxygen species is essential for IL-6 synthesis in response to P. aeruginosa diffusible material. Finally, we uncovered that in CFTRDeltaF508 cells, the extracellular glutathione levels are decreased, leading to a greater sensitivity to reactive oxygen species, providing an explanation for the hyperactivation of the p38 and ERK MAPKs and increased IL-6 synthesis. Taken together, our study has characterized a mechanism whereby the CFTRDeltaF508 mutation in airway epithelial cells contributes to increase inflammation of the airways.

Mutation specific drug therapy for progressive familial or benign recurrent intrahepatic cholestasis: A new tool in a near future?

COMMENTARY ON: Folding defects in P-type ATP 8B1 associated with hereditary cholestasis are ameliorated by 4-phenylbutyrate. van der Velden LM, Stapelbroek JM, Krieger E, van den Berghe PVE, Berger R, Verhulst PM, Holthuis JCM, Houwen RHJ, Klomp LWJ, van de Graaf SFJ. Hepatology 2010;51:286-296. Copyright 2010. Abstract reprinted with permission of John Wiley and Sons, Inc. www.ncbi.nlm.nih.gov/pubmed/19918981 Abstract: Deficiency in P-type ATP8B1 is a severe and clinically highly variable hereditary disorder that is primarily characterized by intrahepatic cholestasis. It presents either as a progressive (pro- gressive familial intrahepatic cholestasis type 1 (PFIC1)) or intermit- tent (benign recurrent intrahepatic cholestasis type 1 (BRIC1)) disease. ATP8B1 deficiency is caused by autosomal recessive mutations in the gene encoding ATP8B1, a putative aminophospho- lipid-translocating P-type adenosine triphosphatase. The exact path- ogenesis of the disease is elusive, and no effective pharmacological therapy is currently available. Here, the molecular consequences of six distinct ATP8B1 missense mutations (p.L127P, p.G308V, p.D454G, p.D554N, p.I661T, and p.G1040R) and one nonsense muta- tion (p.R1164X) associated with PFIC1 and/or BRIC1 were systemat- ically characterized. Except for the p.L127P mutation, all mutations resulted in markedly reduced ATP8B1 protein expression, whereas messenger RNA expression was unaffected. Five out of seven mutations resulted in (partial) retention of ATP8B1 in the endoplasmic reticulum. Reduced protein expression was partially restored by culturing the cells at 30 C and by treatment with proteasomal inhibitors, which indicates protein misfolding and subsequent proteosomal degrada- tion. Protein misfolding was corroborated by predicting the conse- quences of most mutations onto a homology model of ATP8B1. Treatment with 4-phenylbutyrate, a clinically approved pharmacolog- ical chaperone, partially restored defects in expression and localization of ATP8B1 substitutions G308V, D454G, D554N, and in particular I661T, which is the most frequently identified mutation in BRIC1. Conclusion: A surprisingly large proportion of ATP8B1 mutations resulted in aberrant folding and decreased expression at the plasma membrane. These effects were partially restored by treatment with 4-phenylbutyrate. We propose that treatment with pharmacological chaperones may represent an effective therapeutic strategy to ameliorate the recurrent attacks of cholestasis in patients with inter- mittent (BRIC1) disease.

Potential of Curcumin As A Multifunctional Agent to Combat Wilson Disease

We thank Dr. Ji and Dr. Shen for mentioning other potential beneficial effects of curcumin on Wilson disease in addition to the improvement in the membrane expression of mutated copper-transporting adenosine triphosphatase (ATPase) ATP7B proteins that we described.1 Indeed, curcumin has drawn considerable attention recently as an agent with a broad range of properties that might be useful in liver diseases.2 The suggestion by Ji and Shen to conduct rigorous trials of curcumin in Wilson disease therefore seems timely. Nevertheless, some restraint seems appropriate. Even for decoppering agents that have proven effectiveness, such as D-penicillamine, zinc, and trientine, prospective, blinded, randomized clinical trials are lacking.3 As Wilson disease is rare, with an incidence of approximately 1:50,000, any prospective trial will face considerable organizational difficulties. Therefore, when trials are being developed, it seems proper to give priority to improving the evidence for established decoppering agents. We would therefore suggest that the potential of curcumin in Wilson disease should first be explored further in vitro. If it is proven effective, several animal models are available for both Wilson disease and other genetic diseases that cause copper overload (reviewed by Vonk et al.4), and they can subsequently be used to test the potential of curcumin to ameliorate or treat liver disease due to copper overload in vivo. Only when these results are clearly positive should human testing be considered. Dr. Peter V. E. van den Berghe M.D.* , Dr. Roderick H. J. Houwen M.D. , Dr. Leo W. J. Klomp M.D.* , * Departments of Metabolic and Endocrine Diseases, Metabolic Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, the Netherlands, Netherlands Metabolomics Center, Utrecht, the Netherlands.

Tight glycaemic control in the critically ill: losing its grip?

Tight glycaemic control in the critically ill is achieved by administering insulin to target a blood sugar concentration of 4.4–6.1 mmol/litre. This is a valid but controversial target: the Surviving Sepsis campaign currently supports a target of &lt;8.3 mmol/litre. Proof of concept was originally demonstrated by Van den Berghe et al (2001) who recruited 1548 ventilated patients, two thirds post-cardiothoracic surgery, and found tight control reduced mortality from 8.0% to 4.6% (P&lt;0.04), compared to conventional control (&lt;11.9 mmol/litre). There was a 5% incidence of hypoglycaemia (blood glucose &lt;2.2 mmol/litre) in the treatment group. However, subsequent studies, including a second by the same group in medical intensive care patients (Van den Berghe et al, 2006), have failed to replicate these impressive results. Some were terminated early owing to increased mortality and hypoglycaemic episodes (Brunkhorst et al, 2008; Wiener et al, 2008). A meta-analysis by Wiener et al (2008) failed to demonstrate any benefit. NICE-SUGAR, the largest single study performed to date, concluded that tight glucose control may increase mortality (Finfer et al, 2009).

Potential of Curcumin As A Multifunctional Agent to Combat Wilson Disease

Wilson disease (WD) is characterized by copper overload in the liver and basal ganglia and is caused by mutations in the gene encoding protein ATP7B. We read with great interest the article by van den Berghe et al.1 in which they report the beneficial effect of curcumin, the active component of turmeric, in partially restoring protein expression of most ATP7B mutants. Here we propose that, in addition to the ability to enhance the protein expression of ATP7B mutants, several other important properties, such as the antioxidant activity, copper-chelating activity, and superoxide dismutase (SOD) activity of Cu(II)-curcumin complexes, in combination with its pharmacological safety make the natural product curcumin an attractive potential multifunctional agent for the treatment of WD. First, curcumin is an ideal antioxidant and an effective scavenger of reactive oxygen species (ROS) and reactive nitrogen species (RNS).2, 3 It can also inhibit lipid peroxidation and increase glutathione availability.4 As oxidative stress and lipid peroxidation play central roles in the pathogenesis of WD and patients with WD have relevant glutathione depression, curcumin is expected to have beneficial effects by suppressing oxidative stress, preventing lipid peroxidation, and increasing glutathione levels. The antioxidant activity of curcumin has been implicated in its various pharmacological effects. Second, curcumin can act as a copper-chelating agent.5-8 The unique structure of curcumin makes it form complexes of types 1:1 and 1:2 with copper with relatively high binding affinities.5-8 It has been reported that curcumin may bind low micromolar concentrations of copper,5-7 which are much lower than the copper levels in WD. The copper-chelating properties of curcumin have been thought to be involved in its protective effects against Alzheimer's disease,5, 8 which is also characterized by excessive transition-metal ions in the brain. More interestingly, it has been demonstrated that Cu(II)-curcumin complexes possess SOD activity, an ability to neutralize free radicals, and antioxidant potential.6-8 For instance, Cu(II)-curcumin complexes are excellent superoxide radical scavengers and can be regenerated when causing superoxide neutralization.6, 7 This means that after chelating copper, the complexes still possess the ability to alleviate oxidative stress, which is a potential advantage of curcumin in comparison with other copper-chelating agents. In summary, as shown in Fig. 1, the antioxidant and copper-chelating activities, the SOD activity of Cu(II)-curcumin complexes, and the ability to restore the protein expression of most ATP7B mutants imply the potential of curcumin as a multifunctional agent to combat WD. Rigorous trials of curcumin in WD should be conducted to test the therapeutic effect. The intensive preclinical and clinical studies in the past few decades have provided fruitful information on various properties of curcumin,9, 10 such as bioavailability, pharmacodynamics, and pharmacokinetics, which will be helpful for future trials in WD. Potential mechanisms making curcumin a multifunctional agent to combat WD. Hong-Fang Ji*, Liang Shen*, * Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Shandong University of Technology, Zibo, People's Republic of China.

Molecular Identification of Carnosine Synthase as ATP-grasp Domain-containing Protein 1 (ATPGD1)

Carnosine (beta-alanyl-L-histidine) and homocarnosine (gamma-aminobutyryl-L-histidine) are abundant dipeptides in skeletal muscle and brain of most vertebrates and some invertebrates. The formation of both compounds is catalyzed by carnosine synthase, which is thought to convert ATP to AMP and inorganic pyrophosphate, and whose molecular identity is unknown. In the present work, we have purified carnosine synthase from chicken pectoral muscle about 1500-fold until only two major polypeptides of 100 and 90 kDa were present in the preparation. Mass spectrometry analysis of these polypeptides did not yield any meaningful candidate. Carnosine formation catalyzed by the purified enzyme was accompanied by a stoichiometric formation, not of AMP, but of ADP, suggesting that carnosine synthase belongs to the "ATP-grasp family" of ligases. A data base mining approach identified ATPGD1 as a likely candidate. As this protein was absent from chicken protein data bases, we reconstituted its sequence from a PCR-amplified cDNA and found it to fit with the 100-kDa polypeptide of the chicken carnosine synthase preparation. Mouse and human ATPGD1 were expressed in HEK293T cells, purified to homogeneity, and shown to catalyze the formation of carnosine, as confirmed by mass spectrometry, and of homocarnosine. Specificity studies carried out on all three enzymes were in agreement with published data. In particular, they acted with 15-25-fold higher catalytic efficiencies on beta-alanine than on gamma-aminobutyrate. The identification of the gene encoding carnosine synthase will help for a better understanding of the biological functions of carnosine and related dipeptides, which still remain largely unknown.

Jean-Baptiste Labat and the Buccaneer Barbecue in Seventeenth-Century Martinique

If, as the sociologist Pierre L. van den Berghe has suggested, cuisine is a significant expression of man's sociability, one might say that the seventeenth-century missionary Jean-Baptiste Labat was the single most social animal in the Caribbean islands in the 1690s. Although his primary responsibility on the island of Martinique was to serve the island's multiethnic population as a spiritual leader, le père Labat's memoirs chronicle the diverse culinary experiences of the missionary as he literally eats his way around the island, learning to prepare such delicacies as cocoa confit, roasted manatee, lizard en brochette, and parakeet en daube. Positing his unbridled interest in the culinary arts as a mark of his “obedience” to the duties assigned him as missionary, Labat's taxonomy of island delicacies and exotic tastes no doubt titillated the curiosity of his mainland readers while nevertheless grounding itself strongly in the values of order, authenticity, and industry so essential to Labat's apostolic mission. This article focuses on two “buccaneer barbecues” as examples of gastronomical experiences through which Labat was able to construct and negotiate new social, cultural, and symbolic meanings, exploring identity politics through the frame of the culinary arts in seventeenth-century Martinique.

Effectiveness of Tight Glycemic Control in the Medical Intensive Care Unit: A Systematic Review

Effectiveness of Tight Glycemic Control in the Medical Intensive Care Unit: A Systematic Review

Proteome-wide Substrate Analysis Indicates Substrate Exclusion as a Mechanism to Generate Caspase-7 Versus Caspase-3 Specificity

Caspase-3 and -7 are considered functionally redundant proteases with similar proteolytic specificities. We performed a proteome-wide screen on a mouse macrophage lysate using the N-terminal combined fractional diagonal chromatography technology and identified 46 shared, three caspase-3-specific, and six caspase-7-specific cleavage sites. Further analysis of these cleavage sites and substitution mutation experiments revealed that for certain cleavage sites a lysine at the P5 position contributes to the discrimination between caspase-7 and -3 specificity. One of the caspase-7-specific substrates, the 40 S ribosomal protein S18, was studied in detail. The RPS18-derived P6-P5' undecapeptide retained complete specificity for caspase-7. The corresponding P6-P1 hexapeptide still displayed caspase-7 preference but lost strict specificity, suggesting that P' residues are additionally required for caspase-7-specific cleavage. Analysis of truncated peptide mutants revealed that in the case of RPS18 the P4-P1 residues constitute the core cleavage site but that P6, P5, P2', and P3' residues critically contribute to caspase-7 specificity. Interestingly, specific cleavage by caspase-7 relies on excluding recognition by caspase-3 and not on increasing binding for caspase-7.

Spatial patterns of infauna, epifauna, and demersal fish communities in the North Sea

Abstract Reiss, H., Degraer, S., Duineveld, G. C. A., Kröncke, I., Aldridge, J., Craeymeersch, J., Eggleton, J. D., Hillewaert, H., Lavaleye, M. S. S., Moll, A., Pohlmann, T., Rachor, E., Robertson, M., vanden Berghe, E., van Hoey, G., and Rees, H. L. 2010. Spatial patterns of infauna, epifauna, and demersal fish communities in the North Sea. – ICES Journal of Marine Science, 67: 278–293. Understanding the structure and interrelationships of North Sea benthic invertebrate and fish communities and their underlying environmental drivers is an important prerequisite for conservation and spatial ecosystem management on scales relevant to ecological processes. Datasets of North Sea infauna, epifauna, and demersal fish (1999–2002) were compiled and analysed to (i) identify and compare spatial patterns in community structure, and (ii) relate these to environmental variables. The multivariate analyses revealed significantly similar large-scale patterns in all three components with major distinctions between a southern community (Oyster Ground and German Bight), an eastern Channel and southern coastal community, and at least one northern community (&gt;50 m deep). In contrast, species diversity patterns differed between the components with a diversity gradient for infauna and epifauna decreasing from north to south, and diversity hotspots of demersal fish, e.g. near the major inflows of Atlantic water. The large-scale hydrodynamic variables were the main drivers for the structuring of communities, whereas sediment characteristics appeared to be less influential, even for the infauna communities. The delineation of ecologically meaningful ecosystem management units in the North Sea might be based on the structure of the main faunal ecosystem components.

Enteric glial cells protect neurons from oxidative stress in partviareduced glutathione

Enteric glial cells (EGCs) are essential in the control of gastrointestinal functions. Although lesions of EGCs are associated with neuronal degeneration in animal models, their direct neuroprotective role remains unknown. Therefore, the aims of this study were to demonstrate the direct neuroprotective effects of EGCs and to identify putative glial mediators involved. First, viral targeted ablation of EGCs in primary cultures of enteric nervous system increased neuronal death both under basal conditions and in the presence of oxidative stress (dopamine, hydrogen peroxide). Second, direct or indirect coculture experiments of EGC lines with primary cultures of enteric nervous system or neuroblastoma cell lines (SH-SY5Y) prevented neurotoxic effects induced by oxidative stress (increased membrane permeability, release of neuronal specific enolase, caspase-3 immunoreactivity, changes in [Ca(2+)](i) response). Finally, combining pharmacological inhibition and mRNA silencing methods, we demonstrated that neuroprotective effects of EGCs were mediated in part by reduced glutathione but not by oxidized glutathione or by S-nitrosoglutathione. Our study identified the neuroprotective effects of EGCs via their release of reduced glutathione, extending their critical role in physiological contexts and in enteric neuropathies.-Abdo, H., Derkinderen, P., Gomes, P., Chevalier, J., Aubert, P., Masson, D., Galmiche, J.-P., Vanden Berghe, P., Neunlist, M., Lardeux, B. Enteric glial cells protect neurons from oxidative stress in part via reduced glutathione.

All Glucose Measurements Are Not Equal

Dr. Rice et al. have raised a very interesting question about our article published in the March 2009 issue of Anesthesiology,1that concerns the accuracy of the glycemic measurements on capillary blood samples. We agree that the most reliable measurement for blood glucose concentration is on blood samples obtained by arterial line. Generally, the measurement of blood glucose concentration through the HemoCue B-Glucose analyzer (HemoCue, Angelhom, Sweden) with peripheral capillary blood is considered to be reliable in noncritical patients.2,3Thus, previous studies even in critical care patients have used this approach, including the one by Van den Berghe et al. that specified: “The dose of insulin was adjusted according to whole-blood glucose levels, measured at 1- to 4-h intervals in arterial blood or, when an arterial catheter was not available, in capillary blood, with the use of a point-of-care glucometer (HemoCue B-glucose analyzer, HemoCue).”4Our protocol is similar to that of Van den Berghe et al. , but we hypothesized that in our patients population, which is relatively younger than in previous studies, the risk of hypotension, hypoxia, and acidosis is lower.Nevertheless, as we have mentioned in our article, to overcome the risks of this bias we have performed the measurements of blood glucose concentration exclusively on capillary blood samples only in few cases (i.e. , patient in which was difficult to get arterial blood sample: &lt;5% of the measurements). Thus, “in all patients, glucose concentrations were measured in whole blood or on undiluted arterial blood rather than capillary blood samples.” Furthermore, as we reported in the paper, we have made systematic cross controls between blood glucose concentration obtained by arterial and capillary samples and found in our study group nonsignificant differences between the values obtained with the two approaches.*University of Rome, Rome, Italy. bilotta@tiscali.it

Insulintherapie in der Intensivmedizin – Frage nach dem optimalen Blutzucker–Zielbereich bei schwer kranken Patienten

Ever since publication of the spectacular study data of van den Berghe et al. in 2001 on the effect exercised by insulin therapy in the intensive-care ward, the subject of blood sugar control in severely diseased patients has been under heavy cross-fire. At that time a stringently exercised insulin therapy in mainly cardiosurgical patients resulted in a significant reduction of the mortality risk. Therapy algorithms were subsequently modified by numerous intensive-care units and strategies mapped out to utilize the evidence of this initial study. A subsequent publication by the same group already showed in medical intensive-care patients less pronounced advantages offered by a near-normoglycemic metabolism. A large-scale study in patients suffering from sepsis was even discontinued because of increased hypoglycemias under intensive glucose control. Finally, the largest ever study of this problem comprising more than 6 000 intensive-care patients was published under the designation NICE-SUGAR. In this study the 90-day mortality risk was higher with intensive metabolic adjustment than with the control group. Hence, the problem of the most favorable blood sugar target range in intensive-care units remains unsolved. A summing-up of the various items of evidence in a practically useful guideline would be of help to intensive-care units.

Monozygotic multiple gestation after intracytoplasmic sperm injection and preimplantation genetic diagnosis

To report a possible association between intracytoplasmic sperm injection (ICSI)-preimplantation genetic diagnosis (PGD) and monozygotic multiple gestation. Small case series. In vitro fertilization unit in an academic medical center. Three patients were treated with ICSI-PGD for sexing as well as selection against a known translocation. Transfer of day 4 embryos to the uterus. Clinical pregnancy. Two pairs of monozygotic twins and a triplet pregnancy. Repeated manipulation of the zona pellucida as well as extended embryo culture during ICSI-PGD treatments may result in monozygotic twin and triplet pregnancies.

In Search of a Cure: The Patients of the Ghent Homoeopathic Physician Gustave A. Van den Berghe (1837–1902) (review)

In Search of a Cure: The Patients of the Ghent Homoeopathic Physician Gustave A. Van den Berghe (1837–1902) (review)

Preoperative carbohydrate loading: a review of the current evidence

Background: Surgery induces a stress response associated with injury resulting in insulin resistance (Thorell et al., 1999). Fasting is a common procedure presurgery and leads to reduced insulin sensitivity as a result of disturbances in glucose, protein and fat metabolism. Reduced insulin sensitivity has been associated with increased surgical outcome and enhanced patient recovery (van den Berghe et al., 2001). The purpose of this study was to review the current evidence relating to preoperative carbohydrate loading, particularly focusing on outcomes including post‐operative complications, patient well‐being and length of hospital stay.Methods: A structured review was carried out in a systematic manner of randomised clinical trials published between 1998 and 2008 using four medical databases (Medline, CSA Illumni, Pubmed and ISI Web of Knowledge). The available literature published within the last 10 years that measured an objective clinical load was considered for inclusion. Initially, literature searches were commenced using the broad terms ‘preoperative’ and ‘carbohydrate’ (both terms present). This approach was then refined to improve specificity using the following terms in a variety of different combinations: preoperative carbohydrate load; oral carbohydrate; post‐operative period; hospital stay; preoperative nutrition; and treatment outcomes. Exclusion criteria included duplicate records, those not written in English language, animal studies, observational studies with and without controls, protocols, proposals, discussion papers and conference abstracts. The bibliographies of relevant literature were searched for further studies not found by the database searches.Results: A total of 16 randomised control trials were identified from initial searches. Of the 16 that were assessed in full form, three were excluded. The remaining thirteen randomised trials all measured clinical outcomes after a preoperative carbohydrate load 2–3 h prior to elective surgery. The study intervention was similar in each study. The number of patients included in each study varied greatly, from 12 to 252, with seven studies having unequal sample sizes between comparison groups. Nine of the 13 studies had a placebo group, and six studies had a control group. The post‐operative regimen was similar in all thirteen studies and was standardised in studied groups. The clinical, metabolic and nutritional outcomes were reported in all of the studies. Results showed that a preoperative carbohydrate load could reduce post‐operative insulin resistance. Statistical significance was not reached for length of hospital stay, improved well‐being and reduced loss of lean tissue, although trends were seen. None of the trials noted any adverse affects as a result of preoperative carbohydrate load.Discussion: The body of evidence surrounding reduced insulin resistance was of good quality and was consistent with a study by Nygren et al. (1995) where insulin resistance was shown to be reduced by 50% in the same population group. Statistically, individual studies did not provide significant evidence with regard to reduced length of stay, reduced loss of lean muscle mass and patient well‐being. Further research is warranted in all of the reported outcomes because a small sample size has resulted in trends, rather than conclusive evidence. A meta‐analysis may produce more conclusive results.Conclusions: A preoperative oral carbohydrate was associated with several positive outcomes; however, statistical significance was not reached as a result of the small nature of the studies. No adverse affects were associated with a preoperative oral carbohydrate 2–3 h prior to surgery; therefore, overnight fasting guidelines in elective surgery should be questioned.References Nygren, J., Thorell, A., Jacobsson, H., Larsson, S., Schnell, P., Hylen, L. &amp; Ljundqvist, O. (1995) Preoperative gastric emptying: effects of anxiety and oral carbohydrate administration. Ann. Surg.222, 728–734.Thorell, A. Nygren, J. &amp; Ljundqvist, O. (1995) Insulin resistance – a marker of surgical stress. Curr. Opin. Clin. Nutr. Metab Care2, 69–79.Van den Berghe, G., Wouters, P. &amp; Weekers, F. (2001) Intensive insulin therapy in critically ill patients. N. Engl. J. Med.345, 1359–1367.