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.
Subject(s)
Critical Care , Critical Illness/therapy , Growth Hormone/metabolism , Insulin/therapeutic use , Aged , Blood Glucose/drug effects , Blood Glucose/metabolism , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/blood , Chronic Disease , Female , Gene Expression/drug effects , Glycoproteins/antagonists & inhibitors , Human Growth Hormone/metabolism , Humans , Insulin-Like Growth Factor Binding Protein 3/antagonists & inhibitors , Insulin-Like Growth Factor Binding Protein 3/metabolism , Insulin-Like Growth Factor I/antagonists & inhibitors , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Intensive Care Units , Length of Stay , Liver/metabolism , Male , Middle Aged , Peptide Hydrolases/metabolism , RNA, Messenger/metabolism , Receptors, Somatotropin/genetics , Survival AnalysisABSTRACT
IGF binding protein-1 (IGFBP-1), an important regulator of IGF bioavailability, has been shown to correlate with mortality in critically ill patients. In the liver, IGFBP-1 is transcriptionally repressed by insulin, and it is therefore a potential marker of hepatic insulin sensitivity. We have recently shown that, compared with conventional treatment, maintenance of normoglycemia with intensive insulin therapy decreased morbidity and mortality of continuously fed critically ill patients. This study compares the effect of conventional and intensive insulin therapy on IGFBP-1 and assesses its predictive value for mortality. In 363 patients who were dependent on intensive care for more than 7 d and were randomly assigned to either conventional or intensive insulin therapy, serum IGFBP-1 levels were measured on admission, on d 1, 8, 15, 22, and 29, and on the day of intensive care unit discharge or death. In addition, IGFBP-1 and phosphoenolpyruvate carboxykinase mRNA levels were measured by real-time RT-PCR in postmortem liver biopsies obtained from 74 patients who died in the intensive care unit. Although intensive insulin treatment lowered glycemia, it had no effect on IGFBP-1 serum levels. Instead, serum IGFBP-1 concentration was significantly higher in patients who ultimately died, and it differentiated nonsurvivors from survivors 3 wk before death. The predictive value of serum IGFBP-1 for mortality was similar to that of the APACHE-II score. Like circulating IGFBP-1, hepatic mRNA levels of IGFBP-1 and the similarly insulin-regulated gene, phosphoenolpyruvate carboxykinase, were not significantly different between conventional and intensive insulin therapy groups. These data suggest that hepatic insulin resistance in prolonged critically ill patients, reflected by high serum IGFBP-1 levels, is not overcome by intensive insulin therapy, and that this may affect patient outcome.
Subject(s)
Critical Illness , Insulin-Like Growth Factor Binding Protein 1/blood , Aged , Blood Glucose/analysis , Carboxy-Lyases/genetics , Chronic Disease , Critical Illness/mortality , Female , Forecasting , Gene Expression , Humans , Insulin/therapeutic use , Insulin-Like Growth Factor Binding Protein 1/genetics , Intensive Care Units , Length of Stay , Liver/physiopathology , Male , Middle AgedABSTRACT
Several isoquinoline-based templates were identified from the studies of the conformational effects of the diketopiperazine structures for PAI-1 inhibition. Moderate to good activity was retained with the elimination of unattractive characteristics in the diketopiperazine template.
