In our study, we demonstrate that CTRP1 plasma levels are significantly upregulated in critical illness as compared to healthy volunteers, displaying highest levels in patients admitted due to sepsis. Despite increased levels of CTRP1 in pre-existing type 2 diabetes and positive correlation with HbA1c in critically ill patients, we did not find an association with insulin resistance or glucose concentration in the blood. CTRP1 levels in our ICU cohort did not correlate with disease severity or short-term ICU survival, but tend to higher CTRP1 levels. In critically ill patients, CTRP1 levels appeared particularly linked to systemic inflammation, metabolic disturbances and organ dysfunction. The potential pathogenic role of CTRP1 in critical illness and sepsis, however, requires further studies. In general, CTRP1 has been associated with changes in systemic energy metabolism in different metabolic and dietary conditions [28
]. In our cohort of critically ill patients, CTRP1 was indeed related to pre-existing diabetes as well as to long-term blood glucose control reflected by HbA1c, similar to findings in non-ICU patients with diabetes and obesity [14
]. Despite the positive correlation of CTRP1 with BMI, but weak evidence, we found that CTRP1 in critical illness is not associated with a variety of established biomarkers of energy substrate metabolism or diabetes-related cytokines such as insulin, leptin, leptin receptor, ghrelin, adiponectin, resistin or retinol-binding protein 4 (RBP4). The explanation of these findings could potentially be assumed in experimental outcomes of animal models of normal and insulin resistant ob/ob mice. On the one hand, elevated CTRP1 levels lowers blood glucose levels without altering insulin or adiponectin levels [2
], and on the other hand, high CTRP1 concentrations protect from diet-induced obesity and insulin-resistance, while CTRP1 knockout mice developed insulin resistance and hepatic steatosis [6
]. A further key reason besides its protective role against insulin resistance may be the overlapping inflammatory activity in critically ill patients, which we discuss in the following paragraph. Impaired glucose metabolism in CTRP1 knock out-mice was associated with increased hepatic gluconeogenic gene expression, decreased muscle glucose transporter glucose transporter (GLUT) 4 levels and AMP-activated protein kinase activation [11
]. Consistent with its effect in mice, CTRP1 was described to act directly and independently of insulin, and to regulate gluconeogenesis in cultured hepatocytes [2
]. These expected associations between CTRP1 and metabolic parameters likely reflect the physiological, homeostatic functions of CTRP1 before the onset of critical illness. Our study identified additional, unexpected correlations between elevated levels of CTRP1 and inflammation as well as organ failure in ICU patients. CTRP1 is inversely correlated with the glomerular filtration rate (GFR). In addition, we found further positive correlations with urea, creatinine and cystatin C. This association of CTRP1 to renal impairment might be a possible reason for elevated CTRP1 in circulation. This could be due to the retention of CTRP1 in patients with renal insufficiency. CTRP1 correlated significantly with indicative markers of liver damage and cholestasis. These results are presumably related to the corresponding correlation results with parameters of glucose and energy metabolism as well as inflammatory response.
Experimental studies indeed support that CTRP1 is involved in controlling systemic inflammatory responses. In lipopolysaccharide (LPS) stimulated rats, CTRP1 is expressed at high levels in adipose tissues [8
]. The LPS-induced increase in CTRP1 gene expression was found to be mediated by inflammatory cytokines including tumor necrosis factor-α and interleukin 1β [8
]. CTRP1 itself causes a concentration-dependent expression of further inflammatory markers in endothelial and vascular smooth muscle cells [1
], thereby serving as an amplifier of inflammation beyond its tissue of origin. For instance, in heart failure CTRP1 levels in epicardial adipose tissue and blood circulation are elevated [8
]. Elevated CTRP1 levels in circulation increased IL-6 mRNA levels in congestive heart failure and induced aldosterone release through JAK2-STAT3 signaling pathways [8
]. Similar mechanisms may be present in patients with sepsis, where disturbed blood pressure, vascular tone and vascular barrier dysfunction are commonly observed [31
]. On the other hand, CTRP1 administration in experimental CTRP1 knockout mice protected against hyper-inflammation through activation of the S1P/cAMP signalling pathways in cardiomyocytes [6
]. We found a strong correlation of CTRP1 with classical inflammatory parameters such as CRP, procalcitonin and IL-6. Along with the positive correlation between CTRP1 and suPAR, CTRP1 might be induced by the activated immune system [27
]. Despite the close correlation between CTRP1 and inflammatory markers in our study, elevated CTRP1 did not predict an adverse prognosis at the ICU. Thus, further studies are warranted to clarify whether elevated CTRP1 reflect an either harmful or protective endogenous response to critical illness.
In summary, CTRP1 is correlated with several factors such as chronic hyperglycaemia (HbA1c), inflammation (CRP), renal function (creatinine) and liver injury (bilirubin), making it challenging to dissect its clinical relevance from confounding factors. However, although our study included 218 patients, the sample size of our study very likely does not allow to control for all potential confounders.