Circulating retinol binding protein 4 in critically ill patients before specific treatment: prognostic impact and correlation with organ function, metabolism and inflammation

Abstract

IntroductionHyperglycemia and insulin resistance are well-known features of critical illness and impact the mortality rate, especially in sepsis. Retinol binding protein 4 (RBP4) promotes insulin resistance in mice and is systemically elevated in patients with obesity and type 2 diabetes. We investigated the potential role of RBP4 in critically ill patients.MethodsWe conducted a prospective single-center study of serum RBP4 concentrations in critically ill patients. One hundred twenty-three patients (85 with sepsis, 38 without sepsis) were studied at admission to a medical intensive care unit (ICU) before initiation of specific intensive care treatment measures and compared to 42 healthy nondiabetic controls. Clinical data, various laboratory parameters and metabolic and endocrine functions were assessed. Patients were followed for approximately 3 years.ResultsSerum RBP4 was significantly reduced in ICU patients, independently of sepsis, as compared to healthy controls (P < 0.001). Patients with liver cirrhosis as the primary underlying diagnosis for ICU admission had significantly lower RBP4 levels as compared with other ICU patients. Accordingly, in all ICU patients, serum RBP4 closely correlated with liver function and increased with renal failure. No significant differences of serum RBP4 concentrations in septic patients with pulmonary or other origins of sepsis or nonseptic patients could be revealed. Acute phase proteins were inversely correlated with RBP4 in sepsis patients. RBP4 did not differ between patients with or without obesity or preexisting diabetes. However, serum RBP4 levels correlated with endogenous insulin secretion (C-peptide) and insulin resistance (HOMA index). Low serum RBP4 upon admission was an adverse predictor of short-term survival in the ICU, but was not associated with overall survival during long-term follow-up.ConclusionsSerum RBP4 concentrations are significantly reduced in critically ill patients. The strong associations with hepatic and renal function, insulin resistance and acute mortality collectively suggest a role of RBP4 in the pathogenesis of critical illness, possibly as a negative acute phase reactant, and allow a proposition as a potential novel biomarker for ICU patients.

Adipocytokines in Severe Sepsis and Septic Shock

“…As shown in another study the decrease in serum concentrations of RBP4 is independent of the origin of critical illness. There was no difference between concentrations in septic and non-septic patients requiring intensive care medicine, so capillary leakage as a well-known problem in sepsis seems not to be the main reason [92]. Instead, a strong correlation between liver and kidney function and serum RBP4 concentrations was found, reflecting the above mentioned relation of RBP4 to liver and kidney function observed in not critically ill patients [92].…”

“…In critical disease RBP4 serum levels have been found decreased compared to healthy controls, independent of the origin of critical illness [64,92]. During the course of disease, serum levels normalized with resolving critical illness [64].…”

“…Instead, a strong correlation between liver and kidney function and serum RBP4 concentrations was found, reflecting the above mentioned relation of RBP4 to liver and kidney function observed in not critically ill patients [92]. As RBP4 levels were inversely correlated with markers of inflammation, RBP4 seems potentially to be a member of the negative acute-phase reactants described by Richie et al [93], what might be another explanation for decreased levels in critical disease [92]. At present, no association between RBP4 and other adipokines like adiponectin and resistin has been reported, suggesting that the adipose tissue does not contribute to a great extent to serum RBP4 concentrations in critical disease [92].…”

“…There was no difference between concentrations in septic and non-septic patients requiring intensive care medicine, so capillary leakage as a well-known problem in sepsis seems not to be the main reason [92]. Instead, a strong correlation between liver and kidney function and serum RBP4 concentrations was found, reflecting the above mentioned relation of RBP4 to liver and kidney function observed in not critically ill patients [92]. As RBP4 levels were inversely correlated with markers of inflammation, RBP4 seems potentially to be a member of the negative acute-phase reactants described by Richie et al [93], what might be another explanation for decreased levels in critical disease [92].…”

“…As RBP4 levels were inversely correlated with markers of inflammation, RBP4 seems potentially to be a member of the negative acute-phase reactants described by Richie et al [93], what might be another explanation for decreased levels in critical disease [92]. At present, no association between RBP4 and other adipokines like adiponectin and resistin has been reported, suggesting that the adipose tissue does not contribute to a great extent to serum RBP4 concentrations in critical disease [92]. Recently, despite a missing association of RBP4 with preexisting diabetes mellitus or obesity, a study reported a correlation with C-peptide levels, reflecting endogenous insulin production, and with insulin resistance (HOMA index) [92].…”