Serum resistin levels in critically ill patients are associated with inflammation, organ dysfunction and metabolism and may predict survival of non-septic patients

IntroductionBlood glucose levels and insulin resistance in critically ill patients on admission to intensive care units (ICUs) have been identified as factors influencing mortality. The pathogenesis of insulin resistance (IR) in critically ill patients is complex and not fully understood. Resistin is a hormone mainly derived from macrophages in humans and from adipose tissue in rodents, which regulates glucose metabolism and insulin sensitivity. In non-critically ill patients, resistin was found to be related to impaired glucose tolerance, insulin resistance, metabolic syndrome, obesity and type 2 diabetes. Therefore, resistin might represent a link between inflammation, acute phase response and insulin resistance in critically ill patients. We aimed to examine the correlation of serum resistin concentrations to parameters of inflammation, organ function, metabolism, disease severity and survival in critically ill patients.MethodsOn admission to the Medical ICU, 170 patients (122 with sepsis, 48 without sepsis) were studied prospectively and compared with 60 healthy non-diabetic controls. Clinical data, various laboratory parameters, metabolic and endocrine functions as well as investigational inflammatory cytokine profiles were assessed. Patients were followed for approximately three years.ResultsResistin serum concentrations were significantly elevated in all critical care patients compared with healthy controls, and significantly higher in sepsis than in non-sepsis patients. Serum resistin concentrations were not associated with pre-existing type 2 diabetes or obesity. For all critically ill patients, a correlation to the homeostasis model assessment index of insulin resistance (HOMA-IR) was shown. Serum resistin concentrations were closely correlated to inflammatory parameters such as C-reactive protein, leukocytes, procalcitonin, and cytokines such as IL6 and TNF-α, as well as associated with renal failure and liver synthesis capacity. High resistin levels (> 10 ng/ml) were associated with an unfavourable outcome in non-sepsis patients on ICU and the overall survival.ConclusionsSerum resistin concentrations are elevated in acute inflammation due to sepsis or systemic inflammatory response syndrome (SIRS). The close correlation with other acute phase proteins suggests a predominant, clinically relevant resistin release from macrophages in ICU patients. Moreover, resistin could potentially serve as a prognostic biomarker in non-sepsis critically ill patients.

[1]  F. Lönnqvist,et al.  Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance. , 2006, Kidney international.

[2]  T. Forst,et al.  Evaluation of human resistin assays with serum from patients with type 2 diabetes and different degrees of insulin resistance. , 2003, Clinical laboratory.

[3]  S. O’Rahilly,et al.  Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. , 2001, Diabetes.

[4]  F. Tacke,et al.  Resistin Serum Levels Are Associated with Insulin Resistance, Disease Severity, Clinical Complications, and Prognosis in Patients with Chronic Liver Diseases , 2006, The American Journal of Gastroenterology.

[5]  W. Knaus,et al.  Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. 1992. , 2009, Chest.

[6]  T. Yoshikawa,et al.  Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes. , 2004, Clinica chimica acta; international journal of clinical chemistry.

[7]  W. Knaus,et al.  Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. , 1992, Chest.

[8]  M. Lazar,et al.  The hormone resistin links obesity to diabetes , 2001, Nature.

[9]  Rolf Rossaint,et al.  Intensive insulin therapy and pentastarch resuscitation in severe sepsis. , 2008, The New England journal of medicine.

[10]  Anand Rohatgi,et al.  Resistin Is an Inflammatory Marker of Atherosclerosis in Humans , 2005, Circulation.

[11]  Martin L. Lee,et al.  Pronounced elevation of resistin correlates with severity of disease in severe sepsis and septic shock , 2007, Critical care medicine.

[12]  P. Murdock,et al.  Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. , 2003, Biochemical and biophysical research communications.

[13]  D. Stejskal,et al.  Resistin - concentrations in persons with type 2 diabetes mellitus and in individuals with acute inflammatory disease. , 2003, Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia.

[14]  D. Greaves,et al.  Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice. , 2009, The Journal of clinical investigation.

[15]  Joanna D. Holbrook,et al.  Resistin is expressed in human macrophages and directly regulated by PPARγ activators , 2003 .

[16]  C. Mantzoros,et al.  Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes. , 2004, Diabetes care.

[17]  P. Sucharda,et al.  Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. , 2003, European journal of endocrinology.

[18]  Serum resistin (FIZZ3) protein is increased in obese humans. , 2004, The Journal of clinical endocrinology and metabolism.

[19]  Brian W Whitcomb,et al.  Impact of admission hyperglycemia on hospital mortality in various intensive care unit populations* , 2005, Critical care medicine.

[20]  M Schetz,et al.  Intensive insulin therapy in critically ill patients. , 2001, The New England journal of medicine.

[21]  I. Vanhorebeek,et al.  Glucose metabolism and insulin resistance in sepsis. , 2008, Current pharmaceutical design.

[22]  R. Gambino,et al.  Relationships between human serum resistin, inflammatory markers and insulin resistance , 2005, International Journal of Obesity.

[23]  Stephen A. Smith,et al.  Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes. , 2003, The Journal of clinical endocrinology and metabolism.

[24]  S. Kumar,et al.  Serum resistin is associated with C-reactive protein and LDL- cholesterol in type 2 diabetes and coronary artery disease in a Saudi population , 2005, Cardiovascular diabetology.

[25]  A. Kitabchi,et al.  Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. , 2002, The Journal of clinical endocrinology and metabolism.

[26]  F. Tacke,et al.  Insulin resistance in liver cirrhosis is not associated with circulating retinol-binding protein 4. , 2007, Diabetes care.

[27]  S. Kumar,et al.  Resistin, central obesity, and type 2 diabetes , 2002, The Lancet.

[28]  A. Aljada,et al.  Inflammation: the link between insulin resistance, obesity and diabetes. , 2004, Trends in immunology.

[29]  M. Lazar,et al.  Mechanisms of obesity-associated insulin resistance: many choices on the menu. , 2007, Genes & development.

[30]  J. Flier,et al.  The adipocyte as an active participant in energy balance and metabolism. , 2007, Gastroenterology.

[31]  E. Draper,et al.  APACHE II: A severity of disease classification system , 1985, Critical care medicine.

[32]  K. Park,et al.  Plasma resistin concentrations measured by enzyme-linked immunosorbent assay using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus. , 2004, The Journal of clinical endocrinology and metabolism.

[33]  B. Bistrian,et al.  Intensive insulin therapy in critically ill patients. , 2002, The New England journal of medicine.

[34]  G. Van den Berghe,et al.  Intensive insulin therapy in the medical ICU. , 2006, The New England journal of medicine.