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

Alexander Koch, Olav A Gressner, Edouard Sanson, Frank Tacke, Christian Trautwein, Alexander Koch, Olav A Gressner, Edouard Sanson, Frank Tacke, Christian Trautwein

Abstract

Introduction: Blood 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.

Methods: On 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.

Results: Resistin 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-alpha, 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.

Conclusions: Serum 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.

Figures

Figure 1
Figure 1
Serum resistin concentrations in critically ill patients. (a) Serum resistin levels are significantly (P < 0.001, U-test) elevated in all patients in the intensive care unit (n = 170) as compared with healthy controls (n = 60). (b) Serum resistin levels are significantly (P < 0.001, U-test) higher in sepsis patients (n = 122) as compared with non-sepsis (n = 48) patients. Box plots are displayed, where the bold black line indicates the median per group, the box represents 50% of the values, and horizontal lines show minimum and maximum values of the calculated non-outlier values; open circles indicate outlier values.
Figure 2
Figure 2
Association of serum resistin with diabetes and obesity in critically ill patients. (a) Serum resistin levels do not differ between patients with or without pre-existing diabetes mellitus. (b) Serum resistin levels are not associated with obesity as defined by a body mass index of more than 30 kg/m2. Box plots are displayed, where the bold black line indicates the median per group, the box represents 50% of the values, and horizontal lines show minimum and maximum values of the calculated non-outlier values; open circles indicate outlier values. ns = not significant.
Figure 3
Figure 3
Correlation of serum resistin to biomarkers of inflammation in critically ill patients. Serum resistin is strongly correlated with (a) C-reactive protein CRP (r = 0.510, P < 0.001), (b) IL-6 (r = 0.477, P < 0.001), and (c) TNF-α (r = 0.509, P < 0.001). Spearman rank correlation test.
Figure 4
Figure 4
Association of serum resistin with severity of disease and survival in critically ill patients. (a) Serum resistin is correlated with Acute Physiology and Chronic Health Evaluation (APACHE) II score (r = 0.481, P = 0.005, Spearman rank correlation test) as a marker of severity of disease only in non-sepsis patients (n = 48, shown), but not in sepsis patients (n = 122, not shown). (b & c) Serum resistin is a prognostic marker in non-sepsis patients. (b) Kaplan-Meier survival curves of non-sepsis patients are displayed, showing that patients with high serum resistin levels (> 10 ng/ml, black) have an increased mortality ain the intensive care unit as compared with patients with low serum resistin (≤ 10 ng/ml, grey). (c) Kaplan-Meier survival curves of non-sepsis patients are displayed, showing that patients with high serum resistin levels (> 10 ng/ml, black) have an unfavorable prognosis with respect to overall survival as compared with patients with low serum resistin (≤ 10 ng/ml, grey). Marks on the survival curves represent the times of censored observation.

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