Mechanisms of DiseaseProtection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients
Introduction
Hyperglycaemia is common in critically ill patients, as a result of stress-induced insulin resistance and accelerated glucose production.1, 2 Maintenance of normoglycaemia with insulin during intensive care was recently shown to reduce mortality while in the intensive-care unit and in hospital of patients in surgical intensive care. Intensive insulin therapy also improved morbidity,2, 3 reducing the risks of sepsis, excessive inflammation,4 and multiple organ failure, transfusion requirements, and dependence on mechanical ventilation and intensive care. The mechanisms underlying these beneficial clinical effects remain incompletely understood.
Cellular function requires energy supplied by ATP. Under aerobic conditions, most of the ATP necessary to supply organs and tissues with energy is generated by the mitochondrial oxidative phosphorylation system. Electrons derived from oxidation of glucose or fatty acids are transferred through the respiratory-chain complexes I–IV. At complexes I, III, and IV, protons are pumped out of the mitochondrial matrix into the intermembrane space. This action results in the generation of an electrochemical proton gradient, which is used by a fifth enzyme complex (ATP synthase) to drive ATP synthesis. A dysfunctional mitochondrial respiratory chain can affect all organs and tissues and cause a wide variety of disorders.5 Several lines of evidence support the hypothesis that cellular energy metabolism is disturbed in sepsis and critical illness. This disturbance was originally ascribed to inadequate tissue perfusion leading to cellular hypoxia. Recent studies, however, point to a disturbance in oxygen utilisation rather than delivery, which has been labelled “cytopathic hypoxia”.6, 7, 8, 9 Such an abnormality in cellular energy metabolism in critically ill patients is likely to cause organ system dysfunction, the most common cause of death in intensive-care units. In diabetes mellitus, hyperglycaemia-induced overproduction of superoxide by the mitochondrial respiratory chain, inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH), has been linked to vascular damage to organs and tissues.10
Since increased oxidative stress and bioenergetic failure contribute to multiple organ failure in critically ill patients, we hypothesised that a protective effect of intensive insulin therapy on mitochondrial integrity has a role in its potential to improve outcome. We therefore studied mitochondrial ultrastructure, respiratory-chain function, and GAPDH activity in samples of liver and skeletal muscle from patients who had been randomly assigned conventional or intensive insulin therapy.2
Section snippets
Patients
For this study, we selected a subgroup of patients who had been included in a large randomised controlled trial (n=1548) studying the effects of intensive insulin therapy in adult, mechanically ventilated patients admitted to the surgical intensive-care unit.2 In that trial, patients were randomly assigned either intensive insulin therapy to maintain blood glucose concentrations between 4·4 mmol/L and 6·1 mmol/L (normoglycaemia) or conventional insulin therapy, in which insulin was administered
Results
As a consequence of the better survival with intensive insulin therapy, the patients in this treatment group who died had been more severely ill on admission to the intensive-care unit than those in the conventional group. The greater severity is shown by a higher score on the acute physiology and chronic health evaluation (APACHE II)14 during the first 24 h after admission to the intensive-care unit (table 1). They also died sooner. The APACHE II score in the patients assigned intensive
Discussion
Strict maintenance of normoglycaemia with insulin infusion during intensive care beneficially affected the hepatocyte mitochondrial compartment of critically ill patients in a surgical intensive-care unit. The prevention or reversal of mitochondrial ultrastructural abnormalities in hepatocytes with intensive insulin therapy was associated with functional correlates thereof, such as higher activity of respiratory-chain complexes I and IV. By contrast, electron microscopy showed no major
Glossary
- Oxidative stress
- Disequilibrium between pro-oxidants and antioxidants in biological systems.
- Reactive oxygen species
- Reactive intermediates derived from oxygen in aerobic metabolism, either radicals (eg, superoxide anion radical, hydroxyl radical) or non-radical compounds (eg, hydrogen peroxide) able to damage biological macromolecules.
- GLUT-2
- Facilitative glucose transporter present in hepatocytes, renal tubular cells, pancreatic β cells, and gastrointestinal mucosa; it has a high Km and Vmax and
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2021, American Journal of the Medical Sciences