title: Regulation of the somatotropic axis by intensive insulin therapy during protracted critical illness.
abstract: The catabolic state of critical illness has been linked to the suppressed somatotropic GH-IGF-binding protein (IGFBP) axis. In critically ill patients it has been demonstrated that, compared with the conventional approach, which only recommended insulin therapy when blood glucose levels exceeded 12 mmol/liter, strict maintenance of blood glucose levels below 6.1 mmol/liter with intensive insulin therapy almost halved intensive care mortality, acute renal failure, critical illness polyneuropathy, and bloodstream infections. Poor blood glucose control in diabetes mellitus has also been associated with low serum IGF-I levels, which can be increased by insulin therapy. We hypothesized that intensive insulin therapy would improve the IGF-I axis, possibly contributing to the clinical correlates of anabolism. Therefore, 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 the somatotropic axis. Contrary to expectation, intensive insulin therapy suppressed serum IGF-I, IGFBP-3, and acid-labile subunit concentrations. This effect was independent of survival of the critically ill patient. Concomitantly, serum GH levels were increased by intensive insulin therapy. The suppression of IGF-I in association with the increased GH levels suggests GH resistance induced by intensive insulin therapy, which was reflected by the decreased serum GH-binding protein levels. Intensive insulin therapy did not affect IGFBP-3 proteolysis, which was markedly higher in protracted critically ill patients compared with healthy controls. Also, intensive insulin therapy did not suppress the urea/creatinine ratio, a clinical correlate of catabolism. In conclusion, our data suggest that intensive insulin therapy surprisingly suppressed the somatotropic axis despite its beneficial effects on patient outcome. GH resistance accompanied this suppression of the IGF-I axis. To what extent and through which mechanisms the changes in the GH-IGF-IGFBP axis contributed to the survival benefit under intensive insulin therapy remain elusive.
authors.affiliation: Department of Intensive Care Medicine, University Hospital Gasthuisberg, B-3000 Leuven, Belgium. greta.vandenberghe@med.kuleuven.ac.be
authors.forename: Dieter
authors.initials: D
authors.lastname: Mesotten
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Wouters
authors.forename: Robin P
authors.initials: RP
authors.lastname: Peeters
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Hardman
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Holly
authors.forename: Robert C
authors.initials: RC
authors.lastname: Baxter
authors.forename: Greet
authors.initials: G
authors.lastname: Van den Berghe
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000097:blood; D002908:Chronic Disease; D003422:Critical Care; D016638:Critical Illness / Q000628:therapy*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000037:antagonists & inhibitors; D013006:Growth Hormone / Q000378:metabolism*; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000627:therapeutic use*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007362:Intensive Care Units; D007902:Length of Stay; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010447:Peptide Hydrolases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics; D016019:Survival Analysis
chemical_list: D001786:Blood Glucose; D002352:Carrier Proteins; D006023:Glycoproteins; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D012333:RNA, Messenger; D011986:Receptors, Somatotropin; C075944:insulin-like growth factor binding protein, acid labile subunit; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D010447:Peptide Hydrolases; C051815:somatotropin-binding protein