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PRZEGL EPIDEMIOL 2012; 66: 495 - 501
Marek Guzek, Zenon Jakubowski, Piotr Bandosz, Bogdan Wyrzykowski, Marian Smoczyński,
Anna Jabłońska, Tomasz Zdrojewski
ODWROTNY ZWIĄZEK STĘŻENIA BILIRUBINY W SUROWICY Z ZESPOŁEM
METABOLICZNYM I INSULINOOPORNOŚCIĄ U OSÓB DOROSŁYCH W POLSCE
Department of Hypertension and Diabetology , Department of Gastroenterology and Hepatology,
Department of Clinical Chemistry and Biochemistry, Medical University of Gdansk, Poland
STRESZCZENIE
Bilirubina ma potencjalne właściwości antyoksydacyjne i cytoprotekcyjne. Stwierdzono, że jej stężenie
odwrotnie koreluje z chorobami sercowo- metabolicznymi. Niedawno przeprowadzone badania wykazały zwią-
zek stężenia bilirubiny w surowicy z zespołem metabolicznym (ZM) pośród dzieci i młodzieży w USA oraz u
osób dorosłych w Korei . Celem pracy była ocena związku stężenia bilirubiny całkowitej we krwi z zespołem
metabolicznym i insulinoopornością w Polsce
Zbadaliśmy 1568 osób w wieku od 18 do 93 lat. Badane osoby stanowiły reprezentatywną próbę
dorosłych mieszkańców Polski i pochodziły z przekrojowego badania, w trakcie którego oznaczono stężenie
bilirubiny całkowitej w surowicy oraz czynniki ryzyka chorób sercowo- naczyniowych.
Rozpowszechnienie ZM w poszczególnych kwartylach stężenia bilirubiny od pierwszego do czwartego
(95%CI w nawiasach) wynosiło odpowiednio 28.9% (24.5%-33.3%), 32.6% (28.3%-36.9%), 23.4% (19.0%-
27.8%), 21.8% (17.5%-26.2%) (p=0.002). Analiza wieloczynnikowa wykazała, że iloraz szans dla posiadania
ZM w trzecim i czwartym kwartylu bilirubiny wynosił odpowiednio 0.70 (0.50-0.99) i 0.68 (0.48-0.95), przy
przyjęciu najniższego kwartyla stężenia bilirubiny jako referencyjnego. Ze wzrostem liczby spełnionych kryteriów
ZM obserwowano zmniejszanie się średniego stężenia bilirubiny całkowitej w surowicy (p=0,012). W badanej
grupie wykazano również silny, niezależny odwrotny związek stężenia bilirubiny z insulinemią na czczo i insu-
linoopornością (HOMA IR). Iloraz szans dla występowania insulinooporności w czwartym kwartylu bilirubiny
wynosił 0.53 (0.38-0.74) przyjmując najniższy kwartyl bilirubiny jako referencyjny.
U dorosłych osób w Polsce poziom całkowitej bilirubiny w surowicy odwrotnie koreluje z rozpo-
wszechnieniem ZM i insulinoopornością.
bilirubina w surowicy, zespół metaboliczny, insulinooporność
ABSTRACT
Bilirubin has got a potential anti-oxidant, anti-inflammatory and cytoprotective effect. It has
been shown that its concentration is inversely related to cardiometabolic diseases. Recent studies have revealed
the association between serum bilirubin concentrations and metabolic syndrome (MS) among children and ado-
lescents in U.S. and among Korean adults. The aim of this study was to evaluate the association of total serum
bilirubin level with MS and insulin resistance in Poland.
We examined 1568 patients aged 18 to 93 years. The tested population was a nationally representa-
tive sample of Polish adults. They were derived from cross-sectional study, when serum total bilirubin level and
risk factors of cardiovascular diseases were determined.
The prevalence of MS in bilirubin level quartiles (95%CI in parentheses) was 28.9% (24.5%-33.3%),
32.6% (28.3%-36.9%), 23.4% (19.0%-27.8%), 21.8% (17.5%-26.2%) respectively for quartiles 1-4 (p=0.002).
The multivariate analysis showed odds ratio for MS in third and fourth quartile of bilirubin level equal to 0.70
Marek Guzek, Zenon Jakubowski i inni
496 Nr 3
(0.50-0.99) and 0.68 (0.48-0.95) respectively in comparison to the lowest quartile. The more criteria of metabolic
syndrome were fulfilled by the patient, the lower was mean total bilirubin level (p=0.012). In study group there
was also a strong, independent association of bilirubin level with fasting insulin level and insulin resistance
(HOMA-IR). The odds ratio of insulin resistance was 0.53 (0.38-0.74) for the fourth quartile in reference to the
lowest quartile of bilirubin.
In Polish adults serum total bilirubin level is inversely related to the prevalence of MS and
insulin resistance.
serum bilirubin, metabolic syndrome, insulin resistance
INTRODUCTION
Bilirubin, a metabolic end product of heme break-
down, has got potential anti-oxidant, anti-inflammatory
and cytoprotective properties (1) that play a protective
role in various cardiovascular and metabolic diseases.
The studies have shown an inverse relationship of serum
total bilirubin level and risk of coronary artery disease
(CAD) (2,3). In these studies a protective effect of
bilirubin on the risk of CAD was comparable to that of
high-density lipoprotein cholesterol (HDL-C) (2). An
inverse association of serum total bilirubin level with
the severity of CAD and cardiovascular morbidity and
mortality was confirmed (3). An inverse relationship
between serum total bilirubin level and cardiovascular
diseases (CVD), peripheral vascular disease (PVD),
carotid intimal media thickness and stroke was also
shown (4,5,6).
Metabolic syndrome (MS) is a collection of in-
terrelated cardiometabolic risk factors that includes
abdominal obesity, insulin resistance, hypertension and
dyslipidemia. This set of risk factors is connected with
an increased risk of cardiovascular diseases and type
2 diabetes (7). The precise pathogenesis of MS is still
unknown. Insulin resistance , adipokines , oxidative
stress and chronic inflammation are suggested to cause
MS (7,8). Bilirubin itself or via enzymes taking part
in metabolic process of its production may influence
these pathogenetic mechanisms(9,10). Recent study
has revealed an inverse association of bilirubin level
with metabolic syndrome and insulin resistance among
children and adolescents in U.S.(11). Similar inverse
relationship between bilirubin and metabolic syndrome
has been shown among the Korean adult population
(12). Such study has never been performed in adult
population of Caucasians. The aim of our study was to
establish the association of serum bilirubin level with
the prevalence of metabolic syndrome and insulin re-
sistance in a nationally representative sample of adults
from Poland which is a country representing a high risk
for cardiovascular diseases (CVD) in Central-Eastern
Europe region.
MATERIALS AND METHODS
In this study the data of country-representative
sample of adult Polish inhabitants aged 18 to 93 years
was used. Adult population of Poles consists of about 28
million people. The sample was derived from a cross-
-sectional study conducted in 2002, whose main aim was
to evaluate the prevalence of cardiovascular diseases
risk factors in Poland. Multi-stage random sampling
scheme was planned so that each country inhabitant ≥
18 years of age had an identical probability of being
drawn to participate in this study. The respondents lived
in 300 clusters drawn from the territory of the whole
country. Precise algorithm of sampling was previously
described in other reports (13).
Total study sample count was 3051 people. All
records with incomplete laboratory data were exclu-
ded from our analysis. Also subjects with bilirubin
level ≥ 34.2 µmol/L were excluded in order to rule
out patients with impaired liver function. The final
number of analyzed records was 1568 (683 men, mean
age [±SD] 45,8±15,9 years and 885 women, mean age
[±SD] 46,9±16,6 years). The examined sample was
divided into groups according to particular bilirubin
level quartiles.
For each respondent a questionnaire was completed
concerning risk factors of cardiovascular diseases in-
cluding arterial hypertension (AH), diabetes, cigarette
smoking.
Each respondent underwent the following anthro-
pometric measurements: body mass, waist circumferen-
ce, arm circumference and blood pressure.
Waist circumference was measured to the nearest
0.5 cm in a standing position in the widest point per-
pendicularly to the body axis.
Blood pressure was measured using automatic blood
pressure measurement devices Omron M5I, validated
by the Association for the Advancement of Medical
Instrumentation (AAMI). The cuff’s size was adapted
Bilirubin metabolic and insulin resistance 497Nr 3
to the arm circumference of each person examined.
Each respondent had three blood pressure readings
taken during one visit. Mean systolic and diastolic
blood pressure (SBP and DBP) values from the second
and the third measurement were taken for analysis.
People whose mean values were ≥ 140 mmHg or ≥ 90
mmHg respectively and who did not use hypotensive
medication underwent another series of blood pressure
measurements during two following visits in order to
confirm the diagnosis of AH. However, data from the
additional measurements were not used in our study.
Blood samples were collected from people who
gave their consent for the procedure. Respondents
were asked to avoid food and sweet drinks for 12 hours
preceding blood sampling. The samples obtained were
then transported to the local laboratories within 2 hours,
where they were processed in order to obtain serum and
plasma in separate secondary test-tubes.
Material obtained was used for the following ana-
lyses: total cholesterol, HDL-cholesterol, triglycerides,
glucose, bilirubin, insulin and high-sensitive C-reactive
protein (hs-CRP).
Laboratory tests were performed in a certified cen-
tral laboratory with certificate of accreditation number
AB 260 given by the Polish Center of Accreditation
(Polskie Centrum Akredytacji).
Total bilirubin level was determined by a photome-
tric method (Hitachi 911, DIASys Diagnostic Systems
GmbH&Co.KG, Holzheim Germany), total cholesterol
by an enzymatic photometric method (Hitachi 911, FS
10135023, DIASys Diagnostic Systems GmbH&Co.
KG, Holzheim Germany), HDL-cholesterol by direct
enzymatic (Hitachi 911, HDL-Cplus 2nd generation
3030024, Roche Diagnostic GmbH, D-68298 Man-
nheim, Germany), triglycerides by enzymatic colo-
rimetric (FS 10576023, DIASys Diagnostic Systems
GmbH&Co.KG, Holzheim Germany).
Plasma fasting glucose level was measured in
central laboratory by enzymatic method (Hitachi 911,
Glucose Hexokinase FS 10250023, DIASys Diagnostic
Systems GmbH&Co.KG, Holzheim Germany). High-
-sensitive C-reactive protein (hs-CRP) was assessed
by nephelometric method (Behring Nephelometer
100 Analyzer, N High Sensitivity CRP OQIY2, Dade
Behring). Fasting insulin level was evaluated by im-
munoenzymatic method NEIA (Abbott Axsym System,
Abbott Laboratories Diagnostics Division IL 30064,
USA, Insulin Reagent Pack 2D01-20). Fasting insulin
level and insulin resistance (HOMA) were regarded as
elevated when values belonged to the fourth quartile
for the population.
Insulin resistance status was estimated by home-
ostasis model assessment (HOMA-IR) as previously
described (14).
In this study we selected the group of people affec-
ted with MS using its new unified definition that was
published in 2009 (15).
Variables with positively skewed distribution under-
went logarithmic transformation: bilirubin, triglyceri-
des, HDL-cholesterol, hs-CRP, systolic blood pressure
(SBP), diastolic blood pressure (DBP). Reported mean
values were back-transformed.
We compared prevalence of MS and insulin resi-
stance between serum bilirubin quartiles using analysis
of covariance (ANCOVA) with gender included in
model as confounder.
Multivariate analysis was performed to evaluate the
independent relationship between particular MS com-
ponents and bilirubin level. Multiple logistic regression
model was used. The results were given as odds ratio
of particular MS component occurrence depending on
the actual bilirubin quartile group that the respondent
belonged to. Statistical analysis was performed with
use of SAS 9.1 system for Windows (SAS, Cary, NC).
RESULTS
Clinical and biological characteristics of the study
population are presented in table I. Body mass index
(BMI), waist circumference, triglycerides level, total
cholesterol level, systolic and diastolic blood pressure
(SBP and DBP), glucose level, fasting insulin level,
HOMA-IR, hs-CRP and age were higher in patients
with MS. However, HDL-cholesterol level was higher in
people without MS. Bilirubin level was lower in patients
with MS in comparison to those without MS. Univariate
analysis revealed higher mean level of total bilirubin in
men when compared to women (9.75 vs. 8.72 µmol/L,
p<0,0001). There was no association of mean bilirubin
level with subjects’ age observed. Mean bilirubin level
in smokers was lower than in non-smokers (8.55 vs.
9.40 µmol/L , p=0.0009).
According to distribution of bilirubin level in quar-
tiles the prevalence of MS relatively decreased as biliru-
bin level quartiles increased and it was 28.9% (95%CI:
24.5%-33.3%), 32.6% (95%CI: 28.3%-36.9%), 23.4%
(95%CI: 19.0%-27.8%), 21.8% (95%CI: 17.5%-26.2%)
respectively, (p=0.002) – (Fig. 1).
The results of multivariate analysis of relationship
between bilirubin level and MS are presented in table
II. In the study group of people belonging to the third
and the fourth bilirubin level quartile the risk of MS was
lower with OR 0.70 (0.50-0.99) and 0.68 (0.48-0.95)
for the third and fourth quartile respectively when the
lowest quartile of bilirubin level was used as a reference.
Marek Guzek, Zenon Jakubowski i inni
498 Nr 3
In the study population with an increase of MS
criteria fulfilled the decrease of mean serum bilirubin
level was observed (p=0.01) – (Fig. 2).
The results of multivariate analysis of relationship
between bilirubin level and cardiometabolic risk factors
are presented in table II. Among variables analyzed the
strongest negative correlation with bilirubin level was
revealed for triglycerides. The odds ratio of elevated
triglycerides level was 0.39 (0.28-0.55) for the fourth
quartile of bilirubin level in reference to the first one.
In the study population there was an independent
association of bilirubin level with fasting insulin level
and insulin resistance (HOMA-IR). Belonging to the
highest quartile of bilirubin level was connected with
almost half lower risk of having elevated fasting insulin
level – OR=0.55 (0.39-0.76) and insulin resistance –
OR=0.53 (0.38-0.74).
We observed also a strong negative influence of
cigarette smoking on bilirubin level values (see table II).
16
Fig. 1. Prevalence of MS and insulin resistance in relation to serum bilirubin concentration
. (adjusted for gender)
Ryc. 1. Rozpowszechnienie ZM i insulinooporności w zależności od stężenia bilirubiny
w surowicy (skorygowane względem płci)
Q1 Q2 Q3 Q4
Quar ti les o f serum bi lirub in co nce ntrati on
Prevalence of metabolic syndrome [%]
0 10 20 30 40 50
p=0.002
Q1 Q2 Q3 Q4
Quar ti les o f serum bi lirub i n co nce ntrati on
Prevalence of insuli n resistance [%]
0 10 20 30 40 50
p=0.002
Ryc. 2. Średnie stężenie bilirubiny w surowicy w zależności od liczby kryteriów ZM
(skorygowane względem płci)
Fig. 2.. Mean serum bilirubin concentration in relation to the number of MS criteria
(adjusted for gender)
16
Fig. 1. Prevalence of MS and insulin resistance in relation to serum bilirubin concentration
. (adjusted for gender)
Ryc. 1. Rozpowszechnienie ZM i insulinooporności w zależności od stężenia bilirubiny
w surowicy (skorygowane względem płci)
Q1 Q2 Q3 Q4
Quar ti les o f serum bi lirub in co nce ntrati on
Prevalence of metabolic syndrome [%]
0 10 20 30 40 50
p=0.002
Q1 Q2 Q3 Q4
Quar ti les o f serum bi lirub i n co nce ntrati on
Prevalence of insuli n resistance [%]
0 10 20 30 40 50
p=0.002
Ryc. 2. Średnie stężenie bilirubiny w surowicy w zależności od liczby kryteriów ZM
(skorygowane względem płci)
Fig. 2.. Mean serum bilirubin concentration in relation to the number of MS criteria
(adjusted for gender)
Fig. 1. Prevalence of MS and insulin resistance in relation to serum bilirubin concentration (adjusted for gender)
Ryc. 1. Rozpowszechnienie ZM i insulinooporności w zależności od stężenia bilirubiny w surowicy (skorygowane wzglę-
dem płci)
Table I. Comparison of clinical and biological differences between patients with and without MS
Tabela I. Porównanie klinicznych i biologicznych różnic pomiędzy pacjentami z i bez ZM
Variable
Without MS (N=1149) With MS (N=419) p-value for
difference
Estimated
mean 95% LCL 95% UCL Estimated
mean 95% LCL 95% UCL
age [years] 42.1 41.1 43.0 51.9 50.3 53.4 <0.0001
percentage of men 43.4 40.6 46.3 43.9 39.2 48.7 0.8639
bilirubin* [µmol/L] 8.21 7.87 8.38 7.52 7.18 8.04 0.0349
BMI [kg / m²] 24.8 24.5 25.0 29.1 28.7 29.6 <0.0001
waist circumference [cm] 85.2 84.5 85.9 98.5 97.5 99.6 <0.0001
Triglycerides * [mmol/L] 1.12 1.10 1.15 2.13 2.02 2.23 <0.0001
total cholesterol * [mmol/L] 5.11 5.05 5.17 5.69 5.57 5.81 <0.0001
HDL-cholesterol * [mmol/L] 1.46 1.45 1.48 1.17 1.14 1.19 <0.0001
SBP* [mmHg] 129.1 128.0 130.2 144.3 142.2 146.4 <0.0001
DBP * [mmHg] 80.2 79.5 80.9 88.9 87.7 90.2 <0.0001
fasting glucose * [mmol/L] 4.62 4.59 4.65 4.97 4.87 5.07 <0.0001
fasting insulin * [pmol/L] 42.4 40.3 43.7 66.7 62.5 71.5 <0.0001
HOMA IR* 1.24 1.19 1.29 2.13 1.98 2.29 <0.0001
hsCRP * [nmol/L] 10.6 9.9 11.3 18.4 16.7 20.4 <0.0001
Current smoker [%] 34,3 31,5 37,1 32,8 28,1 37,4 p=0.5795
*variables transformed logarithmically
Bilirubin metabolic and insulin resistance 499Nr 3
DISCUSSION
Our cross-sectional country-representative study
has revealed an inverse relationship between serum
total bilirubin level and MS. Our results are consistent
with the report by Lin et al. which presented such a
relationship for children and adolescents in the USA
(11) and with the results of Jo et al. for the adult Korean
population (12). In the latter report such association was
observed both for total serum bilirubin and its fractions,
however the strongest relationship was stated for direct
bilirubin. Likewise, previous study performed among
Koreans revealed the strongest correlation between MS
and direct bilirubin (16). Our report is cross-sectional
country-representative study conducted among Euro-
pean Caucasian adult population.
One of the elements characterizing MS is oxidative
stress. In MS patients an elevation of oxidized LDL
(oxLDL) concentration was found, which is connected
with an increased risk of MS development. Coronary
Artery Risk Development In Young Adults (CARDIA)
study revealed that elevated oxLDL level was associ-
ated with an increased risk of MS to the same degree as
MS components like abdominal obesity, hyperglycemia
and hypertriglyceridemia (17). Bilirubin has got strong
anti-oxidative and anti-inflammatory properties. It
inhibits oxidation of LDL-cholesterol and other lipids,
scavenges free oxygen radicals and counteracts oxida-
tive stress (18).
Bilirubin itself or via molecules taking part in
metabolic process of its production may also influence
other pathogenetic mechanisms of MS. Heme oxygen-
ase (HO) and biliverdin reductase (BVR) take part in
metabolic pathway of bilirubin formation. HO converts
pro-oxidative and pro-atherosclerotic heme into biliver-
din and carbon monoxide (CO). BVR reduces biliverdin
to bilirubin. Bilirubin is oxidized by reactive oxygen
species (ROS) to biliverdin which protects cells from
oxidative stress and then biliverdin is again reduced to
bilirubin by BVR with use of NADPH (1). Experimen-
tal studies on mice and rats with type 2 diabetes and
insulin resistance revealed that induction of HO causes
an increase of adiponektins level, anti-inflammatory
effect, reduction of insulin resistance and improvement
of glucose tolerance (9).Up-regulating HO system
also generates anti-oxidative and anti-atherosclerotic
17
012345
Number of MS criteria
Bilirubin concentration [ mol/l]
024681012
p=0.012
Fig. 2.. Mean serum bilirubin concentration in relation to
the number of MS criteria (adjusted for gender)
Ryc. 2. Średnie stężenie bilirubiny w surowicy w za-
leżności od liczby kryteriów ZM (skorygowane
względem płci)
Table II. Adjusted odds ratios of particular metabolic disorders or risk factors in relation to bilirubin level values (distributed
in quartiles) for the whole study population
Tabela II. Skorygowane ilorazy szans występowania poszczególnych zaburzeń metabolicznych lub czynników ryzyka,
w zależności od wartości stężenia bilirubiny (podział na kwartale) dla całej badanej populacji
Group Q2 vs. Q1 Q3 vs. Q1 Q4 vs. Q1 p-value
Metabolic syndrome11.15 (0.84-1.58) 0.70 (0.50-0.99) 0.68 (0.48-0.95) 0.003
Waist circumference21.55 (1.11-2.15) 1.27 (0.91-1.76) 1.07 (0.77-1.48) 0.042
Triglycerides20.67 (0.49-0.92) 0.49 (0.35-0.69) 0.39 (0.28-0.55) <.0001
HDL- cholesterol20.86 (0.61-1.22) 0.80 (0.56-1.14) 1.05 (0.74-1.50) 0.398
Elevated blood pressure20.86 (0.63-1.18) 0.85 (0.61-1.17) 0.95 (0.69-1.31) 0.709
Hyperglycemia21.15 (0.72-1.84) 1.06 (0.65-1.73) 0.76 (0.44-1.29) 0.441
Insulinemia20.76 (0.55-1.04) 0.66 (0.47-0.91) 0.55 (0.39-0.76) 0.003
HOMA20.81 (0.59-1.11) 0.70 (0.51-0.97) 0.53 (0.38-0.74) 0.003
hs-CRP30.77 (0.54-1.08) 0.70 (0.49-1.01) 0.61 (0.42-0.88) 0.054
Current smoking41.03 (0.76-1.39) 0.72 (0.53-0.98) 0.61 (0.44-0.83) 0.001
95% confidence intervals are given in parentheses.
1Adjusted to age, sex, hs-CRP and current cigarette smoking
2Adjusted to age, sex, hs-CRP, current cigarette smoking and other MS criteria
3Adjusted to age, sex, current cigarette smoking and MS criteria
4Adjusted to age, sex, hs-CRP and MS criteria
Marek Guzek, Zenon Jakubowski i inni
500 Nr 3
products like bilirubin, biliverdin and carbon monoxide
(CO) (1). Oxidative stress is one of etiologic factors of
insulin resistance (19), therefore inverse relationship
between bilirubin and insulin resistance may result from
anti-oxidative properties of these substances. There are
also other hypotheses appearing.
Recent studies have revealed that apart from anti-
-oxidative effect human BVR together with substrates
and products of its activity play a key role in insulin
signal-transduction pathways and in regulation of
gene expression (10). Insulin and insulin-like growth
factor (IGF) act via activation of insulin receptor (IR/
IGFR). Its activity as metabolism and growth factor
regulator depends on protein tyrosine kinases (PTK).
Combination of intracellular domain of insulin receptor
(IR) kinase with its substrate is an initial step of signal
cascade. Insulin receptor tyrosine kinase (IRK) activa-
tion after binding of insulin with extracellular domain
of its receptor is a distinctive signal for proteins that are
insulin receptor substrates (IRS). BVR is a cytoplasm
soluble kinase with double affinity that has an ability of
autophosphorylation and transfer of phosphate groups
to both tyrosine and serine / threonine residues. These
activities of BVR contribute to insulin effect and glu-
cose uptake. There are three observations indicating the
role of BVR in insulin resistance: 1. The presence of
IRS intensifies BVR phosphorylation by IRK; 2. BVR
directly phosphorylates IRS within serine residues; 3.
Insulin-dependant glucose uptake increases when BVR
expression is inhibited by si BVR mRNA. This concept
is supported by the fact that BVR phosphorylates IRS-1
proteins in the regions that are responsible for a decrease
of glucose uptake. There are two effector pathways for
insulin: MAPK i PI3K pathways. MAPK pathway takes
part mainly in the insulin effect on transcription and
mitogenesis, while PI3K influences metabolic proces-
ses. Recent studies suggest the key role of BVR in both
pathways as well as in regulation of protein kinase C
(PKC) isoforms, which constitute a bridge between tho-
se two pathways (20).Our study proved strong inverse
relationship between bilirubin and insulin resistance for
the population of adults. Our results are consistent with
the result obtained by Lin et al. in research conducted
on children and adolescents (11). Similarly, inverse re-
lationship between bilirubin and insulin resistance was
observed by Hwang et al. in their study on adults (16).
Those results may support the conclusion that inverse
association of MS and bilirubin can be caused by its
influence on insulin resistance reduction apart from its
ant-oxidative effect. Further studies are necessary to
explain this issue and to determine the role of bilirubin
or molecules taking part in its production and precise
molecular defects influencing insulin signal-transduc-
tion pathways that cause MS in people.
On the other hand, our research revealed that among
all components of MS the strongest negative correlation
was observed between bilirubin and hypertriglyceride-
mia. This finding supports the observation that serum
bilirubin concentrations might be in association with
serum triglycerides level as a risk factor for CVD (12,16,
21). Additionally, high triglyceride level in association
with low concentration of bilirubin implies the possible
relationship between bilirubin concentration and insulin
resistance. However, some investigators observed no
association between total bilirubin and triglyceride
levels (11,22).
Apart from insulin resistance and triglycerides
there was only an inverse correlation between serum
bilirubin level and cigarette smoking observed out of
all the other cardiovascular risk factors analyzed in our
study. Whereas serum hs-CRP level reached the limits
of statistical analysis (p=0.054), and there was no such
association for arterial blood pressure and glucose level.
Previous reports differ in results concerning rela-
tionship between bilirubin and cardiometabolic risk
factors. Results of some studies show an independent
inverse association of serum total bilirubin level with
cigarette smoking (23), obesity (11,16), arterial blood
pressure, glucose (16), LDL-cholesterol and CRP
(16,21). Findings of other researchers present no such
correlation for arterial blood pressure, glucose , LDL-
-cholesterol and CRP (11,22).
CONCLUSION
This large country-representative study revealed
that among Polish adults bilirubin level within normal
limits or moderately elevated is inversely associated
with prevalence of MS and insulin resistance. The
mechanism of the association between MS and total
bilirubin may be related to the insulin resistance status
but further studies are needed for determination of
the association between serum bilirubin and insulin
resistance.
Study limitations
Our study has several limitations. First, transamina-
ses activities, gamma-glutamyltransferase activity and
viral hepatitis markers were not determined, which does
not allow the precise assessment of potential liver injury
influence on the results obtained. Second, although we
collected data about alcohol drinking, the information
received seems too incomplete and unreliable to be
included in our analysis. Last, since levels of direct and
indirect bilirubin were not determined, it is not possible
to state which type of bilirubin is associated with MS.
Bilirubin metabolic and insulin resistance 501Nr 3
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Received: 12.03.2012 r.
Accepted for publication: 16.07.2012
Marek Guzek
Department of Gastroenterology and Hepatology,
Medical University of Gdansk,
ul. Debinki 7,
80-211 Gdansk, Poland;
telephone number +48 58 3492518,
fax number +48 58 3492522;
e-mail address: guzek.marek@gmail.com
