Elsevier

The Lancet

Volume 365, Issue 9453, 1 January 2005, Pages 53-59
The Lancet

Mechanisms of Disease
Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients

https://doi.org/10.1016/S0140-6736(04)17665-4Get rights and content

Summary

Background

Maintenance of normoglycaemia by use of insulin reduces morbidity and mortality of patients in surgical intensive care. Studies on mitochondrial function in critical illness or diabetes suggest that effects of intensive insulin therapy on mitochondrial integrity contribute to the clinical benefits.

Methods

Enzyme activities of the respiratory-chain complexes and oxidative-stress-sensitive glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were measured by spectrophotometry in 36 snap-frozen samples of liver and skeletal muscle obtained after death from patients who had been randomly assigned intensive (normoglycaemia) or conventional (hyperglycaemia) insulin therapy and who were similar in terms of admission diagnoses and causes of death. Mitochondrial ultrastructure was examined by electron microscopy in a random subgroup (n=20).

Findings

In the liver, hypertrophic mitochondria with an increased number of abnormal and irregular cristae and reduced matrix electron density were observed in seven of nine conventionally treated patients. Only one of 11 patients given intensive insulin treatment had these morphological abnormalities (p=0·005). The effect on ultrastructure was associated with higher activities of respiratory-chain complex I median 1·53 [IQR 1·14–3·01] vs 0·81 [0·54–1·43] U/g liver; p=0·008) and complex IV (1·69 [1·40–1·97] vs 1·16 [0·97–1·40] U/g; p=0·008) in the intensive group than in the conventional group. There was no detectable difference in GAPDH activity. In skeletal muscle, mitochondrial ultrastructure and function were not affected by intensive insulin therapy.

Interpretation

Strict glycaemic control with intensive insulin therapy prevented or reversed ultrastructural and functional abnormalities of hepatocyte mitochondria. The lack of effect on skeletal-muscle mitochondria suggests a direct effect of glucose toxicity and glucose control, rather than of insulin, as the likely explanation.

Relevance to practice

Maintenance or restoration of mitochondrial function and cellular energetics is another therapeutic target, in addition to optimisation of cardiac output, systemic oxygen delivery, and regional blood flow, that might improve outcome for critically ill patients. Our findings could help to explain the mechanism underlying the reduction in mortality found when normoglycaemia was maintained with insulin, and further support use of intensive insulin therapy in this setting.

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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