G. Van den Berghe

Hypoglycaemic effect of AICAriboside in mice

SummaryWe have previously demonstrated that in isolated hepatocytes from fasted rats, AICAriboside (5-amino 4-imidazolecarboxamide riboside), after its conversion into AICAribotide (AICAR or ZMP), exerts a dose-dependent inhibition on fructose-1,6-bisphosphatase and hence on gluconeogenesis. To assess the effect of AICAriboside in vivo, we measured plasma glucose and liver metabolites after intraperitoneal administration of AICAriboside in mice. In fasted animals, in which gluconeogenesis is activated, AICAriboside (250 mg/kg body weight) induced a 50% decrease of plasma glucose within 15 min, which lasted about 3 h. In fed mice, glucose decreased by 8% at 30 min, and normalized at 1 h. Under both conditions, ZMP accumulated to approximately 2 µmol/g of liver at 1 h. It decreased progressively thereafter, although much more slowly in the fasted state. Inhibition of fructose-1,6-bisphosphatase was evidenced by time-wise linear accumulations of fructose-1,6-bisphosphate, from 0.006 to 3.9 µmol/g of liver at 3 h in fasted mice, and from 0.010 to 0.114 µmol/g of liver at 1 h in fed animals. AICAriboside did not significantly influence plasma insulin or glucose utilization by muscle. We conclude that in vivo as in isolated hepatocytes, AICAriboside, owing to its conversion into ZMP, inhibits fructose-1,6-bisphosphatase and consequently gluconeogenesis.

Insulin therapy in the intensive care unit should be targeted to maintain blood glucose between 4.4 mmol/l and 6.1 mmol/l

Hyperglycaemia has been repeatedly associated with risk of mortality and morbidity in the intensive care unit (ICU). However, establishing a causal relationship between hyperglycaemia and adverse outcome requires randomised controlled trials assessing the impact of treating/preventing hyperglycaemia in this condition. The only two randomised controlled studies that have addressed this question so far targeted normoglycaemia (4.4–6.1 mmol/l) in ICUs and showed that the link indeed appears causal. The evidence currently available is thus in favour of a ‘normal ≤6.1 mmol/l’ level for blood glucose control in ICUs and is not supportive of J. Miles’s viewpoint in this debate [1], as studies on any other level have not been performed. The first randomised controlled trial from Leuven included adult patients admitted to ICU after extensive, complicated surgery or trauma, or after medical complications of major surgical procedures [2]. In the intervention group, glucose levels were targeted to 4.4–6.1 mmol/l with a continuous intravenous insulin infusion, resulting in average blood glucose levels of 5.5 mmol/l (normoglycaemia). The control group was treated ‘conventionally’ (only insulin for hyperglycaemia >11.2 mmol/l) and had average blood glucose levels of 8.8 mmol/l. At the start of the study, there were no data available on the size of the expected benefit, and thus interim analysis was performed for safety reasons. The study was stopped after inclusion of 1,548 patients. In the intention-to-treat (ITT) population, the intervention lowered ICU mortality rate from 8.0 to 4.6% [absolute risk reduction (ARR) 3.4%] and in-hospital mortality rate from 10.9 to 7.2% (ARR 3.7%). The benefit was larger in the target population of long-stay patients, with a reduction of ICUmortality rate from 20.2 to 10.6% (ARR 9.6%) and of in-hospital mortality rate from 26.3 to 16.8% (ARR 9.5%). In retrospect, it appeared indeed that the impact of the intervention increased with the duration of its application and that there was a substantial benefit clearly present from 3 days of intensive insulin therapy onwards. Besides saving lives, maintaining normoglycaemia prevented organ failure and shortened time on the ventilator and in the ICU. Maintaining normoglycaemia protected the central and peripheral nervous system and improved longterm rehabilitation of patients with brain injury [3], and evoked substantial cost-savings [4]. A 4 year follow-up of the cardiac surgery patients showed that it also improved long-term outcome with maintenance of the survival rate benefit without inducing additional need for medical care [5]. Subsequently, an observational study in a heterogeneous medical/surgical patient population (n=1,600) confirmed the clinical and cost-saving impact of a tight glucose management protocol in ‘real life’ intensive care [6, 7]. Thereafter, two multi-centre randomised controlled trials were started, but stopped early. The first one was designed as a four-arm study to assess the impact of two types of Diabetologia (2008) 51:911–915 DOI 10.1007/s00125-007-0878-7

Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness

Backgroundu2002 Critical illness results in activation of the hypothalamic–pituitary–adrenal (HPA) axis, which might be accompanied by a peripheral adaptation in glucocorticoid sensitivity. Tissue sensitivity is determined by the active glucocorticoid receptor GRα, of which two splice variants involving the hormone‐binding domain exist, GRβ and GR‐P.

Do we have reliable biochemical markers to predict the outcome of critical illness

Current outcome prediction in critically ill patients relies on the art of clinical judgement and/or the science of prognostication using illness severity scores. The biochemical processes underlying critical illness have increasingly been unravelled. Several biochemical markers reflecting the process of inflammation, immune dysfunction, impaired tissue oxygenation and endocrine alterations have been evaluated for their predictive power in small subpopulations of critically ill patients. However, none of these parameters has been validated in large populations of unselected ICU patients as has been done for the illness severity and organ failure scores. A simple biochemical predictor of ICU mortality will probably remain elusive because the processes underlying critical illness are very complex and heterogeneous. Future prognostic models will need to be far more sophisticated.

Identification of a Purine 5′-Nucleotidase in Human Erythrocytes

In 1975, Paglia and Valentine (1) demonstrated the existence in human erythrocytes of a specific pyrimidine 5′-nucleotidase, which they found inactive on purine nucleotides. A deficiency of this enzyme is known which provokes an hemolytic anemia (reviewed in 2). In accordance with the reported enzymic specificity, the erythrocytes of these patients have markedly elevated concentrations of cytidine and uridine nucleotides but not of purine nucleotides. Although it is evident that dephosphorylation of AMP and IMP should occur in erythrocytes (see Bontemps et al., this volume), the enzyme(s) catalysing this process have hitherto not been identified. This report describes the partial purification and the kinetic properties of a purine-specific 5′-nucleotidase present in human erythrocytes.

The effect of rosiglitazone on asymmetric dimethylarginine (ADMA) in critically ill patients

Asymmetric dimethylarginine (ADMA) plays a crucial role in the arginine-nitric oxide pathway. Critically ill patients have elevated levels of ADMA which proved to be a strong and independent risk factor for ICU mortality. The aim of this study was to investigate the effect of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist rosiglitazone on ADMA plasma levels in critically ill patients. In a randomized controlled pilot study, ADMA, arginine and symmetric dimethylarginine (SDMA) were measured in 21 critically ill patients on the intensive care unit (ICU). Twelve patients received 4mg rosiglitazone once a day for a maximum of 6 weeks or until discharge or death. Nine patients served as control patients. In addition, total sequential organ failure assessment (SOFA score), kidney function and liver function were determined. Compared to the ADMA levels of healthy individuals as specified in earlier studies, ADMA plasma levels of critically ill patients were significantly higher (0.42+/-0.06 versus 0.73+/-0.2micromol/L, respectively; p<0.001). Both ADMA (B=3.5; 95% CI: 0.5-6.5; p=0.023) and SDMA (B=1.7; 95% CI: 0.7-2.7; p=0.001) were independently related to SOFA scores. Overall, rosiglitazone treatment had no effect on ADMA levels, which only significantly differed between the rosiglitazone and control groups at day 7 (p=0.028). The SOFA score in the rosiglitazone group was lower compared to the control group but the difference was only statistically significant at day 10 (p=0.01). In conclusion, in critically ill patients plasma ADMA levels were elevated and associated with the extent of multiple organ failure, but no significant ADMA-lowering effect of the PPAR-gamma agonist rosiglitazone was observed.