Magaly Boussemaere

KU Leuven, Leuven, VLG, Belgium

Are you Magaly Boussemaere?

Claim your profile

Publications (9)53.89 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Critical illness induces swelling, enlargement, and dysfunction of mitochondria, which in liver, but not in muscle, is aggravated by excessive hyperglycemia. We previously demonstrated impaired autophagic clearance of damaged mitochondria in fed prolonged critically ill patients. Impaired fusion/fission-mediated repair and/or renewal through biogenesis may further accentuate mitochondrial abnormalities. We studied mitochondrial fusion/fission and biogenesis and how these are affected by preventing hyperglycemia with insulin during critical illness. Patients admitted to a university hospital surgical/medical intensive-care unit participated in a randomized study. We studied adult prolonged critically ill patients vs. controls. Tolerating hyperglycemia up to 215 mg/dl was compared with intensive insulin therapy targeting normoglycemia (80-110 mg/dl). In liver and skeletal muscle, we quantified levels of several proteins involved in mitochondrial fusion/fission and biogenesis. Key players in mitochondrial fusion/fission and biogenesis were up-regulated in postmortem liver (1.4- to 3.7-fold) and rectus abdominis (1.2- to 4.2-fold) but not in in vivo or postmortem vastus lateralis biopsies of critically ill patients. Maintaining normoglycemia with insulin attenuated the hepatic response in the mitochondrial fusion/fission process but did not affect the markers of mitochondrial biogenesis in liver or muscle. Our observations suggest tissue-dependent attempts of compensatory activation of mitochondrial repair mechanisms during critical illness. Considering the previously observed persistent mitochondrial damage, this activation may be insufficient and contribute to mitochondrial dysfunction. Suppressed activation of fusion/fission when excessive hyperglycemia is prevented with insulin may reflect reduced need for diluting (less) damage during normoglycemia or, alternatively, a suppressive effect of insulin on repair.
    The Journal of clinical endocrinology and metabolism 01/2012; 97(1):E59-64. · 6.50 Impact Factor
  • Source
    Critical Care 01/2011; · 4.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Responses to critical illness, such as excessive inflammation and hyperglycemia, may trigger detrimental chain reactions that damage cellular proteins and organelles. Such responses to illness contribute to the risk of (nonresolving) multiple organ dysfunction and adverse outcome. We studied autophagy as a bulk degradation pathway able to remove toxic protein aggregates and damaged organelles and how these are affected by preventing hyperglycemia with insulin during critical illness. Patients participated in a randomized study, conducted at a university hospital surgical/medical intensive care unit. We studied adult prolonged critically ill patients vs. controls. Interventions: Tolerating excessive hyperglycemia was compared with intensive insulin therapy targeting normoglycemia. We quantified (ultra)structural abnormalities and hepatic and skeletal muscle protein levels of key players in autophagy. Morphologically, both liver and muscle revealed an autophagy-deficiency phenotype. Proteins involved in initiation and elongation steps of autophagy were induced 1.3- to 6.5-fold by critical illness (P ≤ 0.01), but mature autophagic vacuole formation was 62% impaired (P = 0.05) and proteins normally degraded by autophagy accumulated up to 97-fold (P ≤ 0.03). Mitophagy markers were unaltered or down-regulated (P = 0.05). Although insulin preserved hepatocytic mitochondrial integrity (P = 0.05), it further reduced the number of autophagic vacuoles by 80% (P = 0.05). Insufficient autophagy in prolonged critical illness may cause inadequate removal of damaged proteins and mitochondria. Such incomplete clearance of cellular damage, inflicted by illness and aggravated by hyperglycemia, could explain lack of recovery from organ failure in prolonged critically ill patients. These data open perspectives for therapies that activate autophagy during critical illness.
    The Journal of clinical endocrinology and metabolism 01/2011; 96(4):E633-45. · 6.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Targeting normoglycemia with intensive insulin therapy (IIT) improved short-term outcome of pediatric intensive care unit (PICU) patients but increased the incidence of hypoglycemia. Both hyperglycemia and hypoglycemia may adversely affect the developing brain. We studied the impact of targeting normoglycemia with IIT on brain injury markers. This is a preplanned analysis of PICU patients included in a randomized controlled study. The study was conducted at a university hospital PICU. Seven hundred PICU patients participated. Patients were assigned to IIT targeting normal-for-age fasting blood glucose levels or insulin infusion only to prevent excessive hyperglycemia. Serum S100B and neuron-specific enolase (NSE), biomarkers of astrocytic and neuronal damage, respectively, were measured on fixed days (n = 700) and in a nested case-control design before and after hypoglycemia (n = 126). Admission levels of S100B and NSE differed according to diagnosis and illness severity (P < 0.0001). IIT did not affect the time course of these markers. Patients experiencing hypoglycemia in PICU had higher S100B and NSE from admission onward than those without hypoglycemia. In the nested case-control study, both markers decreased after hypoglycemia (P = 0.001 and P = 0.009), unlike in the controls on matched days. IIT in PICU did not evoke neurological damage detectable by circulating S100B and NSE, despite increased incidence of hypoglycemia. Elevated markers in patients with hypoglycemia were not caused by hypoglycemia itself but rather reflect an increased incidence of hypoglycemia in the most severely ill. This hypoglycemia risk appears difficult to capture by classical illness severity scores.
    The Journal of clinical endocrinology and metabolism 10/2010; 95(10):4669-79. · 6.50 Impact Factor
  • Source
    Critical Care 03/2010; · 4.93 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute kidney injury frequently complicates critical illness and increases mortality; maintaining normoglycemia with insulin has been shown to reduce the incidence of intensive care unit (ICU)-acquired kidney injury. Here we tested the mechanisms by which this intervention might achieve its goal, using a rabbit model of burn-induced prolonged critical illness in which blood glucose and insulin were independently regulated at normal or elevated levels. Hyperglycemia caused elevated plasma creatinine and severe morphological kidney damage that correlated with elevated cortical glucose levels. Renal cortical perfusion and oxygen delivery were lower in hyperglycemic/hyperinsulinemic rabbits, compared to other groups, but this did not explain the elevated creatinine. Mitochondrial respiratory chain activities were severely reduced in the hyperglycemic groups (30-40% residual activity), and were inversely correlated with plasma creatinine and cortical glucose. These activities were much less affected by normoglycemia, and hyperinsulinemia was not directly protective. Mitochondrial damage, evident at day 3, preceded the structural injury evident at 7 days. Our study found that hyperglycemia evoked cellular glucose overload in the kidneys of critically ill rabbits, and this was associated with mitochondrial dysfunction and renal injury. Normoglycemia, independent of insulinemia, protected against this damage.
    Kidney International 07/2009; 76(5):512-20. · 8.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In critically ill patients, preventing hyperglycemia (HG) with insulin therapy partially prevented organ dysfunction and protected mitochondria. A study in a rabbit model of critical illness indicated that lower blood glucose level, rather than higher insulinemia, is a key factor in such organ protection. In this model, we now investigated the impact of blood glucose lowering vs. hyperinsulinemia (HI) on mitochondria in relation to organ damage. We assessed whether such effects on mitochondria are mediated indirectly via organ perfusion or directly via reducing cellular glucose toxicity. Prospective, randomized laboratory investigation. University laboratory. Three-month-old male rabbits. After induction of critical illness by burn injury, followed by fluid-resuscitation and parenteral nutrition, rabbits were allocated to four groups, each a combination of normal or elevated blood glucose levels with normal or elevated insulin levels. This required alloxan administration, immediately followed by intravenous insulin and glucose infusions titrated to the respective targets. In liver, the reduced damage by glucose lowering was not explained by better perfusion/oxygen delivery. Abnormal mitochondrial ultrastructure and function was present in the two hyperglycemic groups, most pronounced with concomitant HI. Affected mitochondrial respiratory chain enzyme activities were reduced to 25% to 62% of values in healthy rabbits, in the presence of up to five-fold increased tissue levels of glucose. This was accompanied by elevated levels of dicarbonyls, which may mediate direct toxicity of cellular glucose overload and accelerated glycolysis. The abnormalities were also present in myocardium, although to a lesser extent, and absent in skeletal muscle. In a rabbit model of critical illness, HG evokes cellular glucose overload in liver and myocardium inducing mitochondrial dysfunction, which explained the HG-induced organ damage. Maintenance of normoglycemia, but not HI, protects against such mitochondrial and organ damage.
    Critical care medicine 03/2009; 37(4):1355-64. · 6.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Catecholamines directly stimulate GH, ACTH, and prolactin secretion from rat anterior pituitary through the beta(2)-adrenoceptor (AR). We recently showed that gonadotrophs express the beta(1)-AR and that glucocorticoids drastically increase its mRNA expression level. The present investigation explores whether beta(1)-ARs are functionally coupled to adenylate cyclase. In anterior pituitary cell aggregates, the highly selective beta(1)-AR antagonists CGP 20712A and ICI 89,406-8a attenuated isoproterenol-stimulated cAMP accumulation, but no agonist action of norepinephrine could be detected. Remarkably, CGP 20712A inhibited basal cAMP levels by its own for at least 50%, an action that tended to be more effective in dexamethasone-supplemented medium. The latter effect was abolished by the beta-AR antagonist carvedilol, but not by other beta-AR antagonists. Pretreatment with pertussis toxin abolished the action of CGP 20712A on basal cAMP. CGP 20712A also attenuated isoproterenol-induced cAMP accumulation in the gonadotroph cell lines alphaT3-1 and LbetaT2, but not in the somatotroph precursor cell line GHFT and the folliculo-stellate cell line TtT/GF. However, in LbetaT2 cells CGP 20712A did not inhibit basal cAMP levels by its own. The present data suggest that beta(1)-AR in the anterior pituitary is positively coupled to adenylyl cyclase but is constitutively active in a pertussis toxin-sensitive manner. CGP 20712A may act as an inverse agonist with approximately 50% negative intrinsic activity, suggesting that the beta(1)-AR significantly contributes to basal adenylate cyclase activity in the pituitary.
    Endocrinology 06/2008; 149(5):2391-402. · 4.72 Impact Factor
  • Source
    Critical Care 01/2008; 12. · 4.93 Impact Factor