title: Insufficient activation of autophagy allows cellular damage to accumulate in critically ill patients.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  Patients participated in a randomized study, conducted at a university hospital surgical/medical intensive care unit.
  
  
  METHODS
  We studied adult prolonged critically ill patients vs. controls.
  
  
  METHODS
  Tolerating excessive hyperglycemia was compared with intensive insulin therapy targeting normoglycemia.
  
  
  METHODS
  We quantified (ultra)structural abnormalities and hepatic and skeletal muscle protein levels of key players in autophagy.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Intensive Care Medicine, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. ilse.vanhorebeek@med.kuleuven.be
authors.forename: Ilse
authors.initials: I
authors.lastname: Vanhorebeek
authors.forename: Jan
authors.initials: J
authors.lastname: Gunst
authors.forename: Sarah
authors.initials: S
authors.lastname: Derde
authors.forename: Inge
authors.initials: I
authors.lastname: Derese
authors.forename: Magaly
authors.initials: M
authors.lastname: Boussemaere
authors.forename: Fabian
authors.initials: F
authors.lastname: Güiza
authors.forename: Wim
authors.initials: W
authors.lastname: Martinet
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Timmermans
authors.forename: André
authors.initials: A
authors.lastname: D'Hoore
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Wouters
authors.forename: Greet
authors.initials: G
authors.lastname: Van den Berghe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002452:Cell Count; D002477:Cells / Q000473:pathology*; D016638:Critical Illness / Q000628:therapy; D005260:Female; D006801:Humans; D007328:Insulin / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001786:Blood Glucose; D007328:Insulin