Serum osteocalcin level and its association with carotid atherosclerosis in patients with type 2 diabetes.

0.16 MB·English

by  Sheng, Li

Shengetal.CardiovascularDiabetology2013,12:22 CARDIO
http://www.cardiab.com/content/12/1/22 VASCULAR
DIABETOLOGY
ORIGINAL INVESTIGATION Open Access
Serum osteocalcin level and its association
with carotid atherosclerosis in patients with
type 2 diabetes
Li Sheng1†, Wenjie Cao2†, Bingbing Cha1, Zhaoping Chen1, Fang Wang1 and Jun Liu1*
Abstract
Objective: Toinvestigate theassociation ofserum osteocalcin withcarotid atherosclerosis inpatients with type2
diabetes.
Methods: We performed a cross-sectionalcommunity-based study inmetropolitan area. Serum total osteocalcin
was measured by radioimmunoassay in382 men and 435 postmenopausal women. The carotid artery intima-media
thickness (IMT) and carotid plaques (PLQ) were measuredby B-mode ultrasound.
Results: The crude mean ofserum osteocalcin concentrations were 4.52±2.43 ng/ml for men and 5.75±2.92 ng/ml
for postmenopausalwomen(P <0.001), respectively.Osteocalcin levels were associated inversely with age, fasting
serum insulin,HOMA-IR, ALT, triglycerides, total cholesterol,LDL- cholesterol, CRP (all P<0.001) and positively with
adiponectin and HOMA-B(all P<0.05). After multiple adjustment, theodds ratios (ORs) were substantially higher risk
for carotid plaques (OR 1.77 for 1 SD decrease in osteocalcin, 95% CI 1.23-2.76, p=0.005). These associations
remained significant after further adjustment for potential confounder.
Conclusions: Serum osteocalcin levels is an independentrisk factor for carotid atherosclerosis in patients with type
2diabetes.
Keywords: Osteocalcin, Intima-media thickness, Carotid atherosclerotic plaques, Atherosclerosis
Theincreasedcardiovascularriskintype2diabetesmelli- skeleton unraveled its importance as an endocrine organ.
tus is reflected by atherosclerosis, which is an established A bone-derived protein, osteocalcin, has raised much at-
predictor of coronary heart disease and stroke in older tention as a hormone regulating glucose metabolism and
subjects[1-4].Thisdiabetes-associatedincreaseinathero- fat mass. Recently, osteocalcin has been recognized as a
sclerosis is associated with conventional cardiovascular bone-derived hormone to regulate energy metabolism.
risk factors, such as central obesity, high blood pressure, Osteocalcin knockout mice exhibited glucose intolerance,
anddyslipidaemia,aswellaswithinsulinresistance[5,6]. increased fat mass, insulin resistance, decreased expres-
Osteocalcinisa49-aminoacidbonematrixnoncollagen sion of insulin target genes in liver and muscle, and
proteinexpressedmainlybyosteoblasts[7].Itisaspecific decreased adiponectin gene expression in adipose [11],
biochemicalmarkerof boneturnoverandboneformation whileadministrationofrecombinantosteocalcinincreased
involved in bone mineralization and calcium homeostasis insulin secretion, decreased blood glycaemia and weaken
[8].Studieshaveverifiedthatadiposetissuecouldregulate thedevelopmentofobesity[12].
bone remodeling through the adipokine leptin by acting Previous work has demonstrated that osteocalcin levels
onosteoblasts[9,10].Inturn,bonemodulatesenergyme- areinverselyassociatedwithglucoseandtotaladiponectin
tabolism in a feedback loop. The novel function for the levels,fatmass,andatherosclerosisparametersinpatients
with type 2 diabetes [13]. Furthermore, Chen et al.
*Correspondence:[email protected] observedthatserumosteocalcinlevelsofparticipantswith
†Equalcontributors
self-reported CVD were significantly lower than those
1DepartmentofEndocrinology,ShanghaiFifthPeople’sHospital,Fudan
University,801HeqingRoad,Shanghai,China withoutinmiddle-agedandelderlyChinese[14].Recently,
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acohortstudyhasdemonstratedthatserumosteocalcinis Carotidultrasonography
a strong determinant of severity of coronary atheroscler- Trained technicians performed B mode ultrasonography
osisinChinesemen[15]. using an Acuson Sequoia 512. Images were stored and
In keeping with these observations, it is plausible to read centrally at Shanghai Fifth People’s Hospital Image
consider serum osteocalcin as a promising candidate for Center. The ultrasound scanning protocol in our study
risk assessment and a potential intervention target for was modified in terms of procedures used in previous
diabetic macrovascular diseases. To better evaluate the studies [16,17]. Computer-assisted edge-detection soft-
possible role of serum osteocalcin in the development of ware was not used for measurement of carotid IMT. A
diabeticmacrovasculardiseases,weexaminedtheassoci- lateral view of bilateral images of common carotid arter-
ation of serum osteocalcin levels and development of ca- ies (1 cm proximal to the dilatation of the carotid bulb),
rotidatherosclerosisintype 2diabetes. carotid bulb (identified by the loss of the parallel wall
present in the common carotid artery) and internal ca-
Methods rotid artery (1 cm distal to the tip of the flow divider
Studysample that separates the external and internal carotid arteries)
A cross-sectional study to evaluate the prevalence of dia- was obtained. Sonographers recorded the images and
betic complications in Chinese patients diagnosed with completed ultrasound readings. Intima-media thickness
type2 diabetes agedover 50wasplanned in the Shanghai is the distance between the lumen-intima interface and
downtown residential areas administered by 10 residents’ the media-adventitia interface [18]. Common carotid ar-
committeeswereclustersampledinShanghaicentralarea. tery IMT was defined as the mean of the maximum
Questionnaires to identify diabetes history were sent to IMT in both right and left sides of common carotid ar-
every household in the 10 residential areas and collected tery. Reproducibility was high, with small coefficients of
by primary care clinicians and endocrinologists. The 902 variation(CV)valueofmeasurementofIMT(3.5%).
Chinese patients diagnosed with type 2 diabetes were The plaque of carotid artery (common carotid artery,
identified by questionnaire. The criteria of diagnosis of carotid bulb, and internal carotid artery) is defined as a
type 2 diabetes recommended by ADA in 1997 were localizedprotrusionoftheinternalpartofthevesselwall
adopted. Finally, 817 (90.6%) (382 men and 435 postme- into the lumen of 50% of the surrounding IMT value.
nopausal women)Chinese patients diagnosed with type 2 Plaque presence was defined as ≥1 plaque in any of the
diabetes were enrolled in our study. Written consent was carotid arteries[19].
obtainedfromallparticipants.Thestudywasapprovedby
the Institutional Review Broad of Shanghai Fifth People’s MeasurementsofserumC-reactiveprotein(CRP)and
Hospital,FudanUniversitySchoolofMedicine. totalosteocalcin
The serum CRP were determined in duplicate by ELISA
Datacollection with Duoset kit (DY1707; R&D Systems, Minneapolis,
A standardized questionnaire was used by trained physi- MN) as recommended by the manufacturer. The ELISA
cians to collect information such as age, sex, smoking system had an intraassay coefficient of variation of 3.5-
(yes/no), alcohol drinking (yes/no) and self-reported his- 9.9%andaninterassaycoefficientofvariationof4.1-10.3%,
tory of diabetes, hypertension, dyslipidaemia, coronary respectively. Serum total osteocalcin was measured by
heart disease andstroke. radioimmunoassay(Atom-hitechBeijing,China)withintra
All subjects were assessed after overnight fasting for at and interassay coefficients of variation of 2.4–8.7and
least10h.Anthropometricmeasurementsincludingheight, 2.5–9.5% respectively.
weight, waist circumference, hip circumference and blood
pressure were performed by trained physicians. Body mass Statisticalanalysis
index wascalculated asthe weight in kilograms divided by Normally distributed data were expressed as means ± SD,
thesquareofheightinmetres. whereasvariableswithaskeweddistributionwerereported
as median (interquartile range) and log transformed to
Biochemicalmeasurements approximate normality before analysis. Categorical vari-
Peripheral venous blood samples were collected. Fasting ableswererepresentedbyfrequencyandpercentage.Cor-
plasmaglucose,totalcholesterol,triglycerides,low-density relation coefficients between osteocalcin and metabolic
lipoprotein cholesterol (LDL-c), high-density lipoprotein features were calculated by partial correlation analysis.
cholesterol (HDL-c), serum creatinine, blood urea and Multivariate linear regression models were used to esti-
serum uric acid were measured on an automatic analyzer mate the determinants of IMT. Potential confounding
(Hitachi 7080; Tokyo, Japan). Glycated haemoglobin was variables including age, gender, smoking, duration of dia-
tested by high-pressure liquid chromatography (HLC- betes, BMI, waist circumference, systolic blood pressure,
723G7,Tosoh,Shanghai,China). diastolic blood pressure, CRP, fasting plasma glucose,
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serum creatinine, serum urea, serum cholesterol, LDL-c Table1Generalcharacteristicsoftype2diabeticpatients
andHDL-cwerecontrolledintheregressionmodels.The [Datawerereportedinmean±SDormedian
interaction of confounding variables was assessed. Multi- (interquartilerange)]
variate logistic regression models were used to estimate Male Female
the association of carotid atherosclerotic plaques (PLQ) n 382 435
with osteocalcin. Potential confounding variables includ-
proportionofPLQ(%) 61.5% 52.9%
ing age, gender, smoking, alcohol drinking, self-reported
Age(years) 61.28±11.74 61.60±11.82
CVD, family history of diabetes, eGFR, HbA1c, CRP,
durationofdiabetes(years) 7.51±7.29 7.57±7.61
waist circumference, omeostatic model assessment of in-
sulin resistance (HOMA-IR), waist circumference, and BMI(kg/m2) 24.87±2.78 25.62±3.67*
body mass index (BMI) were controlled in the regression Waistcircumference(cm) 86.75±8.39 82.87±8.91*
models. We defined subjects with no carotid atheroscler- Waist-to-hipratio 0.90±0.08 0.87±0.08*
otic plaques as 0 (n =352), and carotid atherosclerotic
DBP(mmHg) 82.27±11.42 81.45±11.39
plaques as 1 (n =465). All statistical analysis was per-
SBP(mmHg) 138.47±19.62 139.75±21.39
formed with the SPSS Statistical Package (version 13.0;
FPG(mmol/L) 8.52±3.31 8.48±3.27
SPSS Inc., Chicago, IL). A p value of less than 0.05 was
consideredtobestatisticallysignificant. Fastingseruminsulin(μU/ml) 6.78(4.62-10.53) 6.85(4.59-10.13)
HbA1c(%) 7.19±1.66 7.14±1.49
Results Serumuricacid(μmol/L) 315.47±83.29 281.28±69.74*
Generalcharacteristicsofparticipants Serumurea(mmol/L) 6.46±1.91 5.91±1.62*
In all, 817 participants were analyzed, among which 382 Serumcreatinine(μmol/L) 80.23±24.54 60.68±16.76*
were male, 435 were female (Table 1). The average age
Serumcholesterol(mmol/L) 5.11±1.13 5.65±1.12*
was61.46±11.58years.Theaveragedurationoftype2dia-
#Serumtriglycerides(mmol/L) 1.53(1.07-2.22) 1.64(1.15-2.41)
betes was 7.53±7.29 years. Serum triglycerides and CRP
LDL-c(mmol/L) 2.92±0.84 3.122±0.95*
were skew-distributed and had been log transformed to
approximatenormalitybeforeanalysis.Comparetofemale HDL-c(mmol/L) 1.24±0.40 1.38±0.38*
subjects,themalesubjectsexhibitedhigherlevelsofwaist #CRP(mg/l) 2.40(0.89-5.21) 1.75(0.82-5.51)*
circumference (P < 0.05), waist-to-hip ratio (P < 0.05), Abbreviations:DBPdiastolicbloodpressure,SBPsystolicbloodpressure,FPG
serum creatinine (P < 0.05),serum urea (P < 0.05), serum fastingplasmaglucose,LDL-clow-densitylipoproteincholesterol,HDL-chigh-
densitylipoproteincholesterol.
uricacid(P<0.05)andCRP(P<0.05),butlowerlevelsof *P<0.05.
BMI (P < 0.05), adiponectin (P < 0.05), serum cholesterol #Serumfastinginsulin,triglyceridesandCRPwereskew-distributedandhad
(P<0.05),LDL-c(P<0.05)andHDL-c(P<0.05). beenlogtransformedtoapproximatenormalitybeforeanalysis.
even after adjustment for age, gender HbA1c, HOMA-IR
Correlationanalysisoftherelationshipbetween
andserumCRP.
osteocalcinandclinicalvariables
Inthemultivariatelinearregressionmodel,carotidIMT
In spearman analysis, serum osteocalcin correlated with
wassetasdependentvariable,whileage,gender,smoking,
age (r =−0.113, <0.001), CRP (r =−0.073, P=0.031), fasting
alcoholdrinking,durationofdiabetes,BMI,waistcircum-
plasmaglucose(r=−0.085,P<0.001),fastingplasmainsulin
ference, systolic blood pressure, diastolic blood pressure,
(r=−0.155,P<0.001),HOMA-IR(r=−0.145,P<0.001),total
serum osteocalcin, HOMA-IR, CRP, fasting plasma glu-
cholesterol (r =−0.133, P<0.001), triglycerides (r =−0.102,
cose,serumcreatinine,serumurea,serumcholesterol,tri-
P<0.001),andLDL-c(r=−0.087,P=0.014).However,serum
glyceride, HDL-c and LDL-c were set as independent
osteocalcin was not associated with BMI, duration of dia-
variables. We tested the interactions of gender and CRP,
betes,waistcircumference,waist-to-hipratio,systolicblood
genderandTC,genderandTG,genderandLDL-caswell
pressure, diastolic blood pressure, HbA1c and HDL-c (all
as gender and HDL-c, but we failed to find any of signifi-
P>0.05)Table2.
cance. The multivariate linear regression analysis demon-
strated that age, gender, systolic blood pressure, serum
AssociationbetweenserumosteocalcinandIMT osteocalcin, LDL-c and HDL-c were independently asso-
Partialcorrelationanalysisdemonstratedthatserumosteo- ciatedwithcarotidIMT(Table3).
calcin correlated with carotid IMT in diabetic patients
after adjusting for age and gender (r =−0.110, P=0.005). Associationbetweenserumosteocalcinandcarotid
After adjusting for age, gender HbA1c and HOMA-IR, atheroscleroticplaques
osteocalcin still correlated with carotid IMT (r =−0.083, As presented in Table 4, reduced osteocalcin was asso-
P=0.038). This correlation remained (r =−0.080, P=0.043) ciated with increased risk of carotid atherosclerotic
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Table2Correlationbetweenserumosteocalcinandother Table4Theriskofcarotidatheroscleroticplaques
parametersinpatientswithtype2diabetesa associatedwith1SDdecreaseinosteocalcin
Variable Correlationcoefficient Pvalue Model PLQ pvaluea
Age −0.113 <0.001 Total Model1 1.93(1.32-3.01) <0.001
BMI −0.062 0.117 Model2 1.86(1.31-2.95) <0.001
Durationofdiabetes 0.037 0.425 Model3 1.82(1.28-2.94) <0.001
Waistcircumference 0.032 0.479 Model4 1.81(1.24-2.82) <0.001
Waisttohipratio −0.057 0.082 Model5 1.76(1.22-2.77) 0.005
SBP 0.042 0.312 men Model1 2.13(1.41-3.69) <0.001
DBP −0.035 0.457 Model2 2.02(1.50-3.57) <0.001
CRP −0.073 0.031 Model3 1.91(1.32-2.88) <0.001
FPG −0.085 0.025 Model4 1.83(1.27-2.85) <0.001
Fastingplasmainsulin −0.155 <0.001 Model5 1.81(1.25-2.83) <0.001
HbA1c −0.023 0.573 women Model1 1.88(1.29-3.12) <0.001
HOMA-IR −0.145 <0.001 Model2 1.84(1.27-2.99) <0.001
TC −0.133 <0.001 Model3 1.80(1.24-2.98) <0.001
TG −0.102 <0.001 Model4 1.79(1.22-2.92) <0.001
LDL-c −0.087 0.014 Model5 1.75(1.19-2.85) 0.008
HDL-c 0.051 0.074 ValuesareORs(95%CI).
Model1:Unadjusted.Model2:Adjustedforage,sex,smoking(yes/no),alcohol
SBP,systolicbloodpressure;DBP,diastolicbloodpressure;TG,triglycerides;
drinking(yes/no),familyhistoryofdiabetes(yes/no).Model3:Furtheradjusted
TC,totalcholesterol;LDL-c,LDLcholesterol;HDL-C,HDLcholesterol.
forwaistcircumference,HOMA-IR,BMIandwaist/hipratio.Model4:Further
aAllcorrelationcoefficientswerecalculatedafteradjustmentforage,gender.
adjustedforserumtriacylglycerol,totalcholesterol,HDL-andLDL-cholesterol.
Model5:Furtheradjustedforinflammatoryfactors(CRP)andtreatments
plaques.Decreased serum osteocalcin indicated high risk (includingantihypertensivetherapy,antihyperlipidemictherapyand
antihyperglycemictherapy).aFortheriskofPLQ,wedefinedsubjectswithno
for carotid atherosclerotic plaques (OR 1.77 for 1 SD
carotidatheroscleroticplaquesas0,andcarotidatheroscleroticplaquesas1
decrease in osteocalcin, 95% CI 1.23-2.76, p=0.005), after fromtheanalysis.
adjustment for age, gender, smoking, alcohol drinking,
duration of diabetes, BMI, waist circumference, systolic SerumosteocalcincorrelatednegativelywithTGandTC
blood pressure, diastolic blood pressure, serum osteocal- inourstudy,whichisconsistentwithpreviousstudies.Itis
cin, HOMA-IR, CRP, fasting plasma glucose, serum cre- well established that elevated serum TC was an independ-
atinine,serumurea,serumcholesterol,triglyceride,HDL-c ent risk factor for the development of CVD. Given that
andLDL-c. serum osteocalcin levels were significantly associated with
CRP and TC levels, it is plausible to consider osteocalcin
Discussion as a promising candidate for risk assessment and a poten-
In this study, we found that serum osteocalcin levels tialinterventiontargetforCVD.InaJapanesestudy,serum
showed association with the risk of carotid atheroscler- osteocalcin was negatively associated with intima-media
osis from the cross-sectional data in type 2 diabetes. thicknessofcommoncarotidarteryintype2diabeticmen
Moreover, these associations are independent of lifestyle [13]. In another study, serum levels of osteocalcin were
factors, duration of diabetes, family history of diabetes, inversely associated with the metabolic syndrome and the
and,remarkably, CRP,HbA1c,HOMA-IR andBMI. severity of coronary artery disease in Chinese men [15].
Table3Multivariatelinearregressionanalysis:independentpredictorsofcarotidarteryIMTamong817type2
diabeticpatients
Dependentvariable Independentvariables Standardizedcoefficients P Partialr
CarotidIMT Age 0.312 2.5×10-7 0.312
Sex −0.152 2.14×10-2 −0.145
SBP 0.159 9.84×10-3 0.168
Osteocalcin −0.181 4.95×10-3 −0.187
LDL-c 0.142 2.51×10-2 0.148
HDL-c −0.194 3.95×10-3 −0.189
TheabbreviationsarethesameasinTable1.
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Moreover, an Australian study showed that serum osteo- The circulating measure of total osteocalcin includes
calcin levels predicted all-cause and CVD-related mortal- both carboxylated and uncarboxylated forms [35]. Ani-
ity in community-dwelling older men [20]. Interestingly, mal and in vitro data implied that only the uncarboxy-
inlinewithourhypothesis,weobservedthatserumosteo- lated form of osteocalcin functioned hormonally in the
calcin levels is an independent risk factor for carotid ath- regulationofglucosehomeostasisandenergymetabolism.
erosclerosis in patients with type 2 diabetes. Certainly, The latest researches based on population showed that
prospective studies with solid clinical end points are ur- elevated levels of both carboxylated and uncarboxylated
gently needed to clarify whether low osteocalcin level forms of osteocalcin were associated with improved glu-
playsacausalroleinthedevelopmentofatherosclerosis. cosetolerance;buttheuncarboxylatedformwasrelatedto
Endothelial inflammation plays a major role in the insulin secretion, and the carboxylated form was asso-
development of cardiovascular disease (CVD) [21]. The ciated with insulin resistance. Our study only measured
inflammatory process is complex, with various cellular totalosteocalcinanddidnothavemeasurementsofuncar-
mediators known to contribute [22]. We further tested boxylatedosteocalcin;therefore,wecouldnotfurther ver-
the correlation between chronic low-grade inflammation ify this hypothesis. It may be of interest to elucidate this
andosteocalcin.Inourstudy,serumosteocalcincorrelated potentialmechanism inthe contextoftheuncarboxylated
negatively with CRP. CRP is a pattern-recognition mol- and carboxylated forms and determine the direction of
eculeofinnateimmunityasanacute-phasereactantanda causalityinafurtherlongitudinalstudy.
hallmarkoflow-gradesystemicinflammation[23,24].CRP Strengths of this study include the large size of the co-
is a well known serum marker of chronic low-grade in- hort, the use of early morning blood samples to minimise
flammation and has been associated with diabetes, hyper- any effect of diurnal variation on TOC levels and the
tension and CVDs. Hence, the results of current study storage of aliquots at −80°C until assay. We excluded
mightbepartially mediated via the mechanismof chronic men who had conditions known to affect osteocalcin
low-gradeinflammation. levels namely bone fracture, Paget’s disease and use of
Moreover, there is evidence to show the influence of bisphosphonate or glucocorticoid therapy. However, As a
bone proteins on cardiovascular disease [25-33]. During cross-sectional study, there are several limitations. The
atherogenesis, bone matrix proteins, including osteocal- mechanisms underlying these associations are still to be
cin,mayhavearegulatory roleintheatherosclerotic cal- explored. The present findings are inherently limited in
cification process [34]. Recent evidence suggests that theabilitytoeliminatecausalrelationshipsbetweenosteo-
osteoblast-like cells are present in the vasculature and calcin and atherosclerosis. Although most potential con-
capable of calcifying vascular cells. Furthermore, para- founders were carefully controlled, since some of the
crine regulators of bone metabolism such as osteocalcin, study population had several risk factors including hyper-
matrix Gla protein (MGP), osteopontin, and bone mor- tension, and dyslipidemia, we could not eliminate the
phogenetic protein are also present in atherosclerotic ar- possible effect of underlying diseases and medications
teries. Thus, the vascular microenvironment possesses used for these diseases on the present findings. Further
mechanisms similar to those in bone tissues to maintain prospective population-based studies are needed to inves-
mineral homeostasis. Both MGP and osteocalcin are tigatethemechanismsinordertoanswerthesequestions.
known to be Gla-containing proteins. MGP is a secretory In conclusion, our study indicated that serum osteo-
protein with widespread tissue expression, including in calcin levels were significantly associated with carotid
bone and vascular walls. MGP-knockout mice develop atherosclerosis in patients with type 2 diabetes, even
extensive calcification of arteries that rapidly becomes afteradjustmentforotherpotentialconfounders.Thismay
lethal, suggesting that MGP has an antimineralization reflect the role of osteocalcin as a circulating endocrine
role in the artery. In humans, osteocalcin is expressed factor which regulates glucose metabolism and thereby
parallel to MGP in both normal and atherosclerotic cardiovascular risk in patients with type 2 diabetes. Pro-
vessels and is also detected in human carotid arteries spective studies are needed to assess the time course and
fromendarterectomysamples.Thus,thetwoGlaproteins, relevanceofserum osteocalcininthedevelopment ofath-
osteocalcin and MGP, could play a pivotal role in not erosclerosisinpatientswithtype2diabetes.
onlybonemineralizationbutalsovascularwallcalcifica-
tion [13]. However, at present, little is known about
Competinginterests
whether serum osteocalcin secreted from osteoblasts in
Theauthorsdeclarethattheyhavenocompetinginterests.
bone or osteoblast-like cells in vessels actually could
modulateatherosclerosis.Thus,furtherstudiesareneeded
to clarify the pathophysiological processes underlying Authors’contributions
Conceivedanddesignedtheexperiments:JL.Analyzedthedata:LS,WC.
the relationship between serum osteocalcin level and
Contributedreagents/materials/analysistools:LS,WC,BC,ZC,FW.Wrotethe
atherosclerosisparameters. paper:LS,WC.Allauthorsreadandapprovedthefinalmanuscript.
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