Hindawi Publishing Corporation
Mediators of Inflammation
Volume 2013, Article ID 187940, 6 pages
Relationships of Adiponectin with Markers of Systemic
Inflammation and Insulin Resistance in Infants Undergoing
Open Cardiac Surgery
Yukun Cao,1Ting Yang,2Shiqiang Yu,1Guocheng Sun,1Chunhu Gu,1and Dinghua Yi1
1Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, No. 15, Changle West Road,
Xi’an, Shaanxi 710032, China
2Department of Oral Anatomy and Physiology and TMD, School of Stomatology, Fourth Military Medical University, Xi’an,
Shaanxi 710032, China
Correspondence should be addressed to Chunhu Gu; firstname.lastname@example.org and Dinghua Yi; email@example.com
Received 4 August 2012; Accepted 22 May 2013
Academic Editor: Celeste C. Finnerty
Copyright © 2013 Yukun Cao et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background. Insulin resistance and systemic inflammation frequently occur in infants undergoing cardiac surgery with
cardiopulmonary bypass, while adiponectin has been demonstrated to have insulin-sensitizing and anti-inflammatory properties
in obesity and type 2 diabetes mellitus. In this prospective study, we aimed to investigate the association of adiponectin with
insulin resistance and inflammatory mediators in infants undergoing cardiac surgery with cardiopulmonary bypass. Methods
and Results. From sixty infants undergoing open cardiac surgery, blood samples were taken before anesthesia, at the initiation of
open cardiac surgery.
of systemic inflammation 6h after CPB. Conclusions. Although the level of serum adiponectin decreased significantly, there was a
significant inverse association of adiponectin with markers of systemic inflammation and insulin resistance in infants undergoing
assessment of the insulin requirement to maintain euglycaemia and repeated measurements of an insulin glycaemic index. Insulin
Insulin resistance and systemic inflammation frequently
occur in infants undergoing cardiac surgery with cardiopul-
monary bypass (CPB). Insulin resistance presenting with
increased blood glucose level (hyperglycemia) and decreased
sensitivity to insulin increases morbidity and mortality in
critically ill patients [1, 2]. Intensive insulin therapy aiming
at euglycemia improves their clinical outcome [3–5]. In a
recently published study involving patients undergoing car-
diac surgery, intraoperative insulin resistance was associated
with an increased risk of short-term adverse outcomes .
The inflammatory reaction and injury may contribute to the
development of postoperative complications [7, 8]. The mag-
nitude and duration of the systemic inflammatory response
determine the development of tissue damage, multiorgan
failure, or even death [9, 10]. Our previous studies have
demonstrated that ameliorating insulin resistance attenuates
the systemic inflammatory response in infants undergoing
Adiponectin, a hormone derived from the adipose tissue,
has been demonstrated to have insulin-sensitizing and anti-
tus . Recently adiponectin has also been shown to have a
reverse correlation with insulin resistance and inflammatory
mediators . Studies on the relationship of adiponectin
scarce. The present study was undertaken to investigate the
association of adiponectin with the development of insulin
2Mediators of Inflammation
T1 T2T3T4 T5 T6T7
Blood glucose levels (mmol/L)
T1 T2T3 T4 T5T6T7
Serum insulin levels (휇U/mL)
T1T2 T3T4T5T6 T7
Insulin glycaemic index
Figure 1: Changes in blood glucose levels, insulin levels, and insulin glycaemic index in the perioperative period. Reported significances
resistance and kinetic changes of inflammatory mediators in
infants undergoing CPB.
(∗푃 < 0.05,∗∗푃 < 0.01 were calculated using pairwise comparisons with the preoperative level within a repeated measurement analysis of
푇7: 48h after CPB).
2. Materials and Methods
of Xijing Hospital, The Fourth Military Medical University,
and performed according to the World Medical Association
Declaration of Helsinki.
2.1. Patients. Patient population: infants aged between 6
months and 3 years undergoing open cardiac surgery with
CPB for congenital heart disease were enrolled for the study
at our hospital from June 2010 to August 2011. Detailed
information was given to the parents preoperatively and
their written consent was obtained. None of the infants had
a history of diabetes mellitus. Exclusive criteria included
preoperative liver and kidney disease or dysfunction, preop-
erative coagulation disorder, palliative or second operation,
and impaired blood glucose levels.
2.2. Measurements of Insulin Resistance. Overnight fasting
was advised for all patients on the preoperative day. Insulin
resistance was recorded by the individual insulin require-
ments to maintain euglycemia. Blood glucose was monitored
on an hourly basis and insulin infusion rate was adjusted
to maintain glucose levels between 4.4 and 8.3mmol/L. The
infusion of insulin is a standard of care and started when
the glucose concentration became higher than 8.3mmol/L.
An insulin glycaemic index (insulin × glucose/22.5) was
patient as follows: before anesthesia (푇1), at the initiation
calculated at each time point.
2.3. Determination of Insulin, Adiponectin, IL-6, and TNF-훼
CPB (푇7). Serum level of adiponectin was determined with
with an insulin kit (R&D Systems, Abingdon, UK). Plasma
Levels. Blood samples were taken at 7 time points for each
(푇4), 12h after CPB (푇5), 24h after CPB (푇6), and 48h after
Wiesbaden, Germany). Serum insulin levels were measured
of CPB (푇2), at the termination of CPB (푇3), 6h after CPB
a commercial enzyme-linked immunosorbent assay (R&D,
Mediators of Inflammation
Table 1: Baseline characteristics and operative data of infants (푛 =
Male gender (%)
Body weight (kg)
Left ventricular ejection fraction (%)
Cardiopulmonary bypass time (min)
Cross-clamping time (min)
Cardiopulmonary bypass flow (L/min/m2)
5.9 ± 1.7
2.8 ± 0.4
32.7 ± 10.4
1.5 ± 0.4
35.4 ± 4.3
4.6 ± 0.5
67.4 ± 8.6
337 ± 32
19.9 ± 15.7
50.3 ± 7.9
7.8 ± 1.6
9.5 ± 1.2
IL-6 and TNF-훼 levels were determined using commercially
were carried out according to kit guidelines.
Blood glucose level (mmol/L)
Tumor necrosis factor-훼 (pg/mL)
Data are presented as the number (%) of patients or mean values ± SD.
available ELISA kits (R&D Systems, Abingdon, UK) .
All enzyme-linked immunosorbent assay (ELISA) protocols
2.4. Statistical Analysis. All data were expressed as mean
with standard error of the mean. Pearson’s correlation coef-
ficient was estimated for associations between adiponectin
and metabolic variables at different time points. Repeated
measures analysis of variance (ANOVA) models (Figures 1,
2, and 3) were analysed using SPSS version 13.0 (SPSS, Inc.,
Chicago, IL, USA).
3.1. Characteristics of the Study Group. Baseline characteris-
surgery included repair of ventricular septal defects in 35
patients, atrial septal defects in 18 patients, and correction of
tetralogy of Fallot in 7 patients.
3.2. Kinetics of Insulin Resistance. Blood glucose was moni-
tored on an hourly basis throughout the observation period.
All patients required insulin treatment to maintain eugly-
caemia. Figure 1(a) shows the stable blood glucose levels
throughout the observation period. Serum insulin concen-
trations increased at the termination of CPB, following the
course of exogenously applied insulin, and remained stable
thereafter (Figure 1(b)). To create a more specific parameter
insulin levels, we calculated an insulin glycaemic index
(insulin × glucose/22.5) at each time point (Figure 1(c)). The
reflecting the kinetics of exogenously applied insulin.
insulin glycaemic index increased during the first 22 hours
of the observation period and remained stable thereafter
Table 2: Correlations of adiponectin with metabolic variables.
with the insulin
initiation of CPB; 푇3: termination of CPB; 푇4: 6h after CPB; 푇5: 12h after
with IL -6
significance test are both presented. (푇: time; 푇1: before anesthesia; 푇2:
CPB; 푇6: 24h after CPB; 푇7: 48h after CPB.∗푃 < 0.05 and∗∗푃 < 0.001.)
period inflammatory cytokines rapidly increased with peak
Pearson’s correlation coefficient (푟) and 푃 values of the corresponding
concentrations of TNF-훼 and IL-6 at the 6h time point (Fig-
the 6h time point (Figure 3).
ures 2(a) and 2(b)). Adiponectin serum levels were repressed
throughout the observation period reaching a minimum at
3.4. Correlations of Adiponectin with Metabolic Variables at
Different Time Points. There was no association between
the adiponectin at 푇3, 푇5, 푇6, and 푇7 time points and
was 푟 = −0.465 (푃 < 0.001) was adiponectin with IL-6,
Correlation of adiponectin with the insulin glycaemic index
푟 = −0.447 (푃 < 0.001).
with insulin glycaemic index, IL-6, and TNF-훼 (Figure 4).
푟 = −0.427 (푃 < 0.001), and adiponectin with TNF-훼 was
Several studies have reported that adiponectin has a negative
correlation with insulin resistance in chronic diseases such
as metabolic syndrome and type 2 diabetes [15, 16]. How-
ever, the relationship of adiponectin with insulin resistance
and inflammatory mediators in infants undergoing cardiac
so far. The present study demonstrated the correlation of
adiponectin with insulin resistance and the kinetic changes
of inflammatory cytokines in infants undergoing CPB. CPB
provokes a systemic inflammatory response. This inflamma-
tory reaction may contribute to the development of postop-
erative complications. The marked increases in the amount
of exogenous insulin requirement to maintain euglycemia as
well as circulating insulin levels during CPB surgery suggest
the development of insulin resistance. Our study showed
significant increase in TNF-훼 and IL-6 levels after the initi-
to maintain euglycemia following the operation suggested
the development of insulin resistance. Insulin resistance is
ation of CPB and their kinetics at various time points. At the
same time, the need of an increased rate of insulin infusion
4Mediators of Inflammation
IL-6 levels (pg/mL)
T1T2 T3T4 T5T6T7
TNF-훼 levels (pg/mL)
Figure 2: Pre- and postoperative TNF-훼 and IL-6 (∗푃 < 0.05,
∗∗푃 < 0.01 compared with basal levels). The error bars designate
standard deviation. IL-6 and TNF-훼 levels are higher than basal levels and did not normalize within the study period ((a) and (b)). (CPB:
cardiopulmonary bypass; 푇: time; 푇1: before anesthesia; 푇2: initiation of CPB; 푇3: termination of CPB; 푇4: 6h after CPB; 푇5: 12h after CPB;
푇6: 24h after CPB; 푇7: 48h after CPB).
T1 T2T3T4T5 T6 T7
Adiponectin levels (휇g/mL)
Reported significances (∗푃 < 0.05 was calculated using pairwise
ferent time points). The error bars designate the standard deviation
comparisons with the preoperative level within a repeated measure-
ment analysis of variance model for the respective parameter at dif-
(CPB: cardiopulmonary bypass; 푇: time; 푇1: before anesthesia; 푇2:
after CPB; 푇6: 24h after CPB; 푇7: 48h after CPB).
associated with the inflammatory response, but its molecular
basis and physiological significance are not fully understood.
acids [17, 18]. Insulin resistance would be more intense as
inflammatory mediator levels increase.
Adiponectin has been shown to directly or indirectly
affect insulin sensitivity through modulation of insulin sig-
naling and the molecules involved in glucose and lipid
metabolism . Adiponectin-deficient mice were shown
or through synergistic effect could lead to the development
of insulin resistance by blocking the signal transduction of
to be prone to diet-induced obesity and insulin resis-
tance and its reversal by adiponectin treatment . In
humans, low adiponectin was more closely associated with
insulin resistance than adiposity . In infants undergo-
ing cardiac surgery, IL-6 and TNF-훼 levels were markedly
increased while serum adiponectin levels were moderately
decreased. This suggests the inverse relationship of circulat-
ing adiponectin levels to IL-6 and TNF-훼 and insulin resis-
adiponectin levels were associated with high inflammatory
levels and intense insulin resistance. This indicates the role
of adiponectin in regulation of glucose metabolism (insulin
resistance) and inflammatory mediators.
tance in critically ill patients. The repression of adiponectin
serum levels in our model and its association with insulin
In summary, we have demonstrated the significant inverse
association of adiponectin with markers of systemic inflam-
mation and insulin resistance in infants undergoing open
cardiac surgery. The better understanding of the association
of adiponectin with insulin resistance and systemic inflam-
Yukun Cao and Ting Yang contributed equally to this paper.
Medicine Foundation of Xijing Hospital (no. XJZT11Z08).
Mediators of Inflammation5
r = −0.427
P < 0.001
IL-6 levels (pg/mL)
r = −0.447
P < 0.001
TNF-훼 levels (pg/mL)
r = −0.465
P < 0.001
Insulin glycaemic index
Figure 4: Correlations of adiponectin at 푇4 (6h after CPB) with IL-6 (a), TNF-훼 (b), and insulin glycaemic index (c). Pearson’s correlation
coefficient (푟) and 푃 values of the corresponding significance test are both presented.
 S. O. Butler, I. F. Btaiche, and C. Alaniz, “Relationship between
hyperglycemia and infection in critically ill patients,” Pharma-
cotherapy, vol. 25, no. 7, pp. 963–976, 2005.
 I. Vanhorebeek, L. Langouche, and G. van den Berghe,
“Glycemic and nonglycemic effects of insulin: how do they
contribute to a better outcome of critical illness?” Current
Opinion in Critical Care, vol. 11, no. 4, pp. 304–311, 2005.
 G. van den Berghe, P. Wouters, F. Weekers et al., “Intensive
insulin therapy in critically ill patients,” The New England
Journal of Medicine, vol. 345, no. 19, pp. 1359–1367, 2001.
 G. van den Berghe, A. Wilmer, G. Hermans et al., “Intensive
insulin therapy in the medical ICU,” The New England Journal
of Medicine, vol. 354, no. 5, pp. 449–461, 2006.
 R. Zheng, C. Gu, Y. Wang et al., “Impacts of intensive insulin
therapy in patients undergoing heart valve replacement,” Heart
Surgery Forum, vol. 13, no. 5, pp. E292–E298, 2010.
T. Schricker, “The association of preoperative glycemic control,
intraoperative insulin sensitivity, and outcomes after cardiac
surgery,” Journal of Clinical Endocrinology and Metabolism, vol.
95, no. 9, pp. 4338–4344, 2010.
 H. Aebert, S. Kirchner, A. Keyser et al., “Endothelial apoptosis
is induced by serum of patients after cardiopulmonary bypass,”
The European Journal of Cardio-thoracic Surgery, vol. 18, no. 5,
pp. 589–593, 2000.
of endothelial progenitor cells responsible for postnatal vascu-
Circulation Research, vol. 85, no. 3, pp. 221–228, 1999.
of endotoxin lethality in mice,” Science, vol. 285, no. 5425, pp.
 K. J. Tracey, Y. Fong, D. G. Hesse et al., “Anti-cachectin/TNF
monoclonal antibodies prevent septic shock during lethal bac-
teraemia,” Nature, vol. 330, no. 6149, pp. 662–664, 1987.
inflammatory mediators in infants undergoing cardiac surgery
with cardiopulmonary bypass,” Cytokine, vol. 44, no. 1, pp. 96–
 F. Ziemke and C. S. Mantzoros, “Adiponectin in insulin
resistance: lessons from translational research,” The American
Journal of Clinical Nutrition, vol. 91, no. 1, pp. 258S–261S, 2010.
 M. Lehrke, U. C. Broedl, I. M. Biller-Friedmann et al., “Serum