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Contribution of Circulating Lipids to the Improved Outcome of Critical Illness by Glycemic Control with Intensive Insulin Therapy

Department of Intensive Care Medicine (D.M., P.J.W., G.V.d.B.) and Laboratory for Experimental Medicine and Endocrinology (J.V.S., F.V.), University Hospital Gasthuisberg, Catholic University Leuven, B-3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Greet Van den Berghe, M.D., Ph.D., Department of Intensive Care Medicine, University Hospital Gasthuisberg, B-3000 Leuven, Belgium. E-mail: greta.vandenberghe{at}med.kuleuven.ac.be.

Compared with the conventional approach, which recommended only insulin therapy when blood glucose levels exceeded 12 mmol/liter, strict maintenance of blood glucose levels less than 6.1 mmol/liter with intensive insulin therapy has shown to reduce intensive care mortality, acute renal failure, critical illness polyneuropathy, and bloodstream infections in critically ill patients by about 40%. This study of 363 patients, requiring intensive care for more than 7 d and randomly assigned to either conventional or intensive insulin therapy, examines the effects of intensive insulin therapy on glucose and lipid homeostasis and their respective impact on the improved outcome. Intensive insulin therapy effectively normalized blood glucose levels within 24 h, both in survivors and nonsurvivors. Intensive insulin therapy also increased serum levels of low-density lipoprotein (P = 0.007) and high-density lipoprotein (P = 0.005), whereas it suppressed the elevated serum triglyceride concentrations (P < 0.0001). Multivariate logistic regression analysis, corrected for baseline univariate risk factors and the effect on inflammation, indicated that lipid rather than glucose control independently determined the beneficial effects of intensive insulin therapy on morbidity and mortality. In postmortem biopsies obtained from 74 patients who died in the intensive care unit, intensive insulin therapy increased mRNA levels of skeletal muscle glucose transporter 4 (P = 0.02) and hexokinase (P = 0.03), unlike those of hepatic glucokinase. In conclusion, our data suggest that intensive insulin therapy normalizes blood glucose levels through stimulation of peripheral glucose uptake and concomitantly partially restores the abnormalities in the serum lipid profile, which may have contributed significantly to the improved outcome of protracted critical illness.

This work was supported by the Fund for Scientific Research, Flanders, Belgium (G.0144.00 and G.0278.03) and the Research Council of the Catholic University of Leuven (OT 03/56). D.M. is a Research Assistant (aspirant) and G.V.d.B. a Fundamental Clinical Research Investigator (G.3C05.95N) for the Fund for Scientific Research (Flanders, Belgium). G.V.d.B. holds an unrestrictive Catholic University of Leuven Novo Nordisk Chair of Research.

Abbreviations: APACHE II, Acute physiology and chronic health evaluation II; CI, confidence interval; CRP, C-reactive protein; CV, coefficient of variation; GK, glucokinase; GLUT-4, glucose transporter 4; HDL, high-density lipoprotein; HXK-II, hexokinase II; LDL, low-density lipoprotein; LPL, lipoprotein lipase; OR, odds ratio; SREBP-1c, sterol regulatory element binding protein 1c; VLDL, very LDL.

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