association of serum adiponectin with diabetic microvascular complications among south indian type 2...

Clinical Biochemistry xxx (2014) xxx–xxx

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Clinical Biochemistry

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Association of serum adiponectin with diabetic microvascularcomplications among south Indian type 2 diabeticsubjects — (CURES-133)

R. Pradeepa, J. Surendar, K. Indulekha, S. Chella, R.M. Anjana, V. Mohan ⁎Madras Diabetes Research Foundation & Dr. Mohan's Diabetes Specialities Centre, WHO Collaborating Centre for Non-communicable Diseases Prevention & Control, IDF Centre of Education,Gopalapuram, Chennai, India

⁎ Corresponding author at: Madras Diabetes ResearDiabetes Specialities Centre, WHO Collaborating Centre fPrevention & Control & IDF Centre for Education, GopalaFax: +91 44 2835 0935.

E-mail address: [email protected] (V. MohanURL: http://www.drmohansdiabetes.com (V. Mohan)

http://dx.doi.org/10.1016/j.clinbiochem.2014.10.0090009-9120/© 2014 The Canadian Society of Clinical Chem

Please cite this article as: Pradeepa R, et al, As2 diabetic subjects — (CURES-133), Clin Bioc

a b s t r a c t
a r t i c l e i n f o
Article history:
Received 22 July 2014Received in revised form 20 October 2014Accepted 23 October 2014Available online xxxx
Keywords:Serum adiponectinDiabetic retinopathyNeuropathyNephropathyCURESType 2 diabetesSouth Indians

Objectives: To assess the association of serum adiponectin andmicrovascular complications of diabetes in anurban south Indian type 2 diabetic population.

Design and methods: Diabetic subjects [n = 487] were included from Chennai Urban Rural EpidemiologyStudy (CURES). Four-field stereo retinal color photography was done and diabetic retinopathy (DR) wasclassified as non-proliferative DR (NPDR) or proliferative DR (PDR) according to the Early Treatment DiabeticRetinopathy Study grading system. Sight threatening DR (STDR) was defined as the presence of NPDR withdiabetic macular edema, and/or PDR. Neuropathy was diagnosed if vibratory perception threshold of the greattoe using biothesiometry exceeded ≥20 V. Nephropathy was diagnosed if urinary albumin excretion (UAE)was ≥30 μg/mg creatinine. Serum total adiponectin levels were measured by radioimmunoassay.

Results: Subjects with any microvascular complications had significantly higher levels of adiponectin levelscompared to those without the complications (geometric mean: 6.1 vs. 5.3 μg/mL, p = 0.004). The adiponectinlevel was significantly higher in subjects with DR (6.8 vs. 5.5 μg/mL, p = 0.004) and neuropathy (5.6 vs.6.5 μg/mL, p= 0.024) compared to those without. Adiponectin levels were not significantly different in subjects
with andwithout nephropathy. Serum adiponectin levels increasedwith the severity of DR [No DR— 5.5 μg/mL;NPDRwithout DME— 6.5 μg/mL; STDR— 8.3 μg/mL, p = 0.001]. Regression analysis revealed adiponectin to beassociated with microvascular disease (presence of neuropathy and/or retinopathy and/or nephropathy)(OR: 1.44, 95% CI: 1.01–2.06, p = 0.049) even after adjusting for age, gender, BMI, HbA1c, diabetes of duration,serum cholesterol and triglycerides, hypertension and medication status.
Conclusion: In Asian Indianswith type 2 diabetes, serum adiponectin levels are associatedwithmicrovascularcomplications and also with the severity of retinopathy.

© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Introduction

Diabetic complications represent a significant cause of morbidityand mortality in diabetic patients [1] and some of the characteristiccomplications include retinopathy, nephropathy and neuropathy.Adiponectin is themost abundant adipocytokine secreted in the adiposetissue and has been shown to be decreased in conditions such as obesity[2], insulin resistance [3], and type 2 diabetes mellitus (T2DM) [4]. Italso has anti-atherogenic [5], anti-inflammatory [6], and insulin sensi-tizing [7] functions and hence by improving hyperglycemia, it could

ch Foundation & Dr. Mohan'sor Non-communicable Diseasespuram, Chennai 600 086, India.

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ists. Published by Elsevier Inc. All rig

sociation of serum adiponecthem (2014), http://dx.doi.org

affect the development and progression of diabetic microangiopathy. Italso helps to modulate vascular function and various inflammatory pro-cesses [8]. However, the association between serum total adiponectinand diabetic microangiopathy is controversial and the results fromexisting reports are inconsistent [9,10].

Overexpression of adiponectin has been shown to attenuate patho-logical retinal and choroidal neovascularization [11,12] suggesting thatit may be a potential alternative therapy for the treatment of retinalvascular diseases. However, the association of adiponectinwith diabeticretinopathy is still largely unknown. Conflicting results regarding thelevels of adiponectin in patients with retinopathy have been reported[9,10].

Recent reports suggest that serumand urinary adiponectin levels areincreased in T2DM patients with overt nephropathy [13]. It is alsoknown that plasma adiponectin levels increased in primary nephroticsyndrome [14]. The literature on the levels of adiponectin in diabeticneuropathy is scanty and one study has shown that higher serum

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in with diabetic microvascular complications among south Indian type/10.1016/j.clinbiochem.2014.10.009

http://dx.doi.org/10.1016/j.clinbiochem.2014.10.009

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2 R. Pradeepa et al. / Clinical Biochemistry xxx (2014) xxx–xxx

adiponectin levels were associated with an increased probability ofcardiac autonomic neuropathy [15].

The aims of the present study were to look at the levels ofadiponectin in patients with and without diabetic retinopathy,nephropathy and neuropathy and to assess the association ofadiponectin with the severity of diabetic retinopathy in an AsianIndian population.

Subjects and methods

Study subjects were recruited from the Chennai Urban Rural Epide-miology Study (CURES), conducted on a representative population ofChennai (formerly Madras), in southern India using systematic randomsampling technique. The details of the sampling and methods of thestudy are published elsewhere [16]. Details of the sampling aredescribed on our website (http://www.mdrf.in/misc/CURES.pdf). Brief-ly, in Phase 1, a detailed questionnaire was used to obtain basic demo-graphic data and fasting capillary blood glucose using a One TouchBasic glucose meter (LifeScan Johnson & Johnson, Milpitas, California,USA) in 26,001 randomly selected individuals aged 20 years andabove from Chennai. Self reported diabetic subjects identified in Phase1 (n = 1529) were classified as ‘known diabetic (KD) subjects’ basedon a physician diagnosis of diabetes and current use of medicationsfor diabetes (insulin or oral hypoglycemic agents).

In Phase 2 of CURES, all the KD subjects (n = 1529) were invited toour center for detailed studies on vascular complications. In addition,15% of those with impaired fasting glucose (IFG; n = 817) and 10% ofthosewith normal fasting glucose (n= 1560) fromPhase 1were subject-ed to an oral glucose tolerance test (OGTT) using a 75 g oral glucose load(dissolved in 250 mL of water) [n = 2870]. 371 subjects were identifiedto have diabetes from these groups and were treated as NDD subjectsbased on the WHO criteria [2 hour plasma glucose ≥ 200 mg/dL(≥11.1 mmol/dL)] [17]. For this study, 487 diabetic subjects (375known diabetic [KD] subjects and 112 newly detected diabetic [NDD]subjects), who had gradable retinal photographs, albuminuria estima-tions, biothesiometry studies and serum adiponectin measurementsfrom Phase 2 of CURES were included for analysis (Fig. 1). Approval ofthe institutional ethics committee of the Madras Diabetes ResearchFoundation was obtained for the study and written informed consentwas obtained from all study subjects.

Fig. 1. Subject selection from Chennai Urba

Please cite this article as: Pradeepa R, et al, Association of serum adiponect2 diabetic subjects — (CURES-133), Clin Biochem (2014), http://dx.doi.org

Anthropometric and clinical measurements

Anthropometric measurements, including weight, height, and waistcircumference, were obtained using standardized techniques [16]. Thebody mass index (BMI) was calculated using the formula: weight (kg)/ height (m2). Blood pressure was recorded in the sitting position inthe right arm with a mercury sphygmomanometer (Diamond DeluxeIndustrial Electronics and Products, Pune, India) and rounded off tothe nearest 2 mm Hg. Two readings were taken 5 min apart andthe mean of the two was taken as the final blood pressure reading.Hypertension was diagnosed in subjects whowere on antihypertensivemedication or had systolic BP≥ 140mmHg or diastolic BP≥ 90mmHg[18].

Biochemical parameters

A fasting blood sample was taken for the estimation of plasma glu-cose and serum lipids after an overnight fast of 8 h using a Hitachi 912autoanalyzer (Roche Diagnostics GmbH, Mannheim, Germany).Glycated hemoglobin (HbA1c) was measured by the High PerformanceLiquid Chromatography (HPLC) method using the Variant machine(BIORAD, Hercules, California). Fasting adiponectin levels weremeasured by radioimmunoassay (catalog number HADP-61HK, LincoResearch, St. Charles, MO). The intra- and inter-assay coefficients ofvariation were 3.8% and 7.4%, respectively, and the lower detectionlimit was 1 ng/mL.

Urine samples were collected after an overnight fast. Microalbuminconcentration was measured using an immunoturbidometric assay(Hitachi 902 autoanalyzer, Roche Diagnostics, Mannheim, Germany).Nephropathy was diagnosed if the albumin excretion was ≥30 μg/mgof creatinine (microalbuminuria — 30-299 μg/mg of creatinine andmacroalbuminuria — ≥300 μg/mg of creatinine) [19].

Retinal photography

The ocular fundi were photographed using four-field stereo colorretinal photography [Zeiss FF 450 plus camera] by trained and certifiedphotographers [20]. Photographs were graded by an ophthalmologistusing the Early Treatment Diabetic Retinopathy Study [ETDRS]grading system [21]. The minimum criterion for the diagnosis of

n Rural Epidemiology Study (CURES).


http://www.mdrf.in/misc/CURES.pdf


3R. Pradeepa et al. / Clinical Biochemistry xxx (2014) xxx–xxx

diabetic retinopathy (DR) was the presence of at least one definitemicroaneurysm in any field photographed. Photographs wereassessed and assigned a retinopathy level, and the final diagnosisfor each patient was determined from the grading of the worse eyeaccording to the ETDRS criteria for the severity of disease in the indi-vidual eye. Briefly, according to the ETDRS grading, level 10 repre-sents no retinopathy, level ≥20 non-proliferative DR (NPDR) andlevel ≥60 proliferative DR (PDR) [21]. Diabetic Macular Edema(DME) was defined as retinal thickening at or within 1 disc diameterof the center of the macula or the presence of definite hard exudates.Sight threatening DR (STDR) or severe DR was defined as the pres-ence of NPDR with DME, and/or PDR. In this study the severity ofDR was categorized as No DR, NPDR without DME and STDR.

Biothesiometry studies

A biothesiometer (Biomedical Instrument Co., Newbury, Ohio, USA)was used to assess vibratory perception threshold (VPT) of the greattoes in a standardized fashion. Neuropathy was diagnosed if VPT ofthe great toe exceeded mean + 2 SD of healthy non-diabetic studypopulation aged 20–45 years (cut point ≥ 20 V) [22].

Statistical analysis

All statistical analyses were performed using SPSS version15.0 for Windows (SPSS, Inc., Chicago, IL). Data are expressed asmean ± SD or geometric mean (95% confidence interval [CI]) incase of non-normally distributed parameters. Adiponectin valueswere log transformed to induce normality of distribution. Trend chisquare test was used to compare proportions among groups. Theassociation of serum adiponectin with microvascular complicationswas analyzed using multiple logistic regression analysis with micro-vascular complications as the dependent variable. Multinomialregression analysis was done using No DR, NPDR without DME andSTDR as the dependent variables and serum adiponectin as theindependent variable. Similarly multinomial regression analysiswas done using the severity of nephropathy (normal albuminuria,microalbuminuria and macroalbuminuria) as the dependent vari-able. Different models were constructed to determine associationby adjusting for common risk variables. A p value b 0.05 was consid-ered significant.

Table 1Clinical and biochemical characteristics of the study subjects.

Variables Without microvascular complic

Age [years] 45.7 ± 9.5Male n [%] 104 (47.1)Waist [cm] 92.1 ± 9.6Body mass index [kg/m2] 26.1 ± 4.2Systolic blood pressure [mm Hg] 124.0 ± 16.0Diastolic blood pressure [mm Hg] 78.0 ± 11.0Fasting plasma glucose [mg/dL] 145.0 ± 55.1Glycated hemoglobin [%] 8.2 ± 1.9Duration of diabetes [years] 3.5 ± 4.5Total serum cholesterol [mg/dL] 199.0 ± 36.0Serum triglycerides [mg/dL]⁎ 146.8High density lipoprotein [HDL] cholesterol [mg/dL] 41.8 ± 9.3Low density lipoprotein [LDL] cholesterol [mg/dL] 125.0 ± 32.6Microalbuminuria [μg/dL]⁎ 7.8Adiponectin [μg/mL]⁎ 5.3Medicationa

Only diet 14 (9.1)Oral hypoglycemic agents n (%) 132 (85.7)Insulin n (%) 8 (5.2)

p b 0.05 is significant and marked in bold⁎ Geometric mean.⁎⁎ p for trend.a Medication details provided for known diabetic subjects [n = 154 for subjects without mi


Results

Of the 487 diabetic subjects studied, DR was present in 81 (16.6%)[NPDR — 68 (14.0%); STDR — 13 (2.6%)], nephropathy in 143 (29.4%)[microalbuminuria — 140 (28.8%); macroalbuminuria — 3 (0.6%)] andneuropathy 138 (28.3%) of the subjects. 266 (54.6%) had either one ormore microvascular complications. Among this group, 16 subjects(6.0%) had all three microvascular complications of diabetes, while 64subjects (24.1%) had twomicrovascular complications and 186 subjects(69.9%) had only one complication. Among the total subjects, 375 wereknown diabetic [KD] subjects and 112 were newly detected diabetic[NDD] subjects There was no difference in the levels of adiponectinbetween the newly diagnosed and known diabetic subjects (5.5 vs5.8 μg/mL; p = 0.286).

Table 1 shows the clinical and biochemical features of the studygroup classified by the presence of microvascular disease. Comparedwith the subjects with no microvascular complications, subjects withone or more microvascular complications were older (p b 0.001), hadsignificantly higher duration of diabetes (p b 0.001), systolic blood pres-sure (p b 0.001), fasting plasma glucose (p b 0.001), HbA1c (p b 0.001)and serum adiponectin levels (p = 0.006). Serum adiponectin levelsincreased significantly with increasing number of microvascular compli-cations [no microvascular complications— 5.4 μg/mL; one microvascularcomplication— 6.1 μg/mL; two ormore complications— 6.3 μg/mL, trendp = 0.019] (Fig. 2).

Fig. 3 presents the serum adiponectin levels in subjects with andwithout diabetic microvascular complications in the study population.The adiponectin level in subjects with DR (6.8 μg/mL) was significantlyhigher (p = 0.004) than those without DR (5.5 μg/mL). Similarly theadiponectin level in subjects with neuropathy was significantly higherthan those without neuropathy (5.6 vs. 6.5 μg/mL, p = 0.024) respec-tively. In the case of subjects with nephropathy also, adiponectin levelswere higher than those with nephropathy, but the difference did notreach statistical significance.

Fig. 4 presents the serum adiponectin levels in relation to the se-verity of DR. An increasing trend of serum adiponectin levels was ob-served with increasing severity of DR [No DR — 5.5 μg/mL; NPDR —

6.5 μg/mL; STDR— 8.3 μg/mL, p for trend 0.001]. Multinomial regres-sion analysis was done using No DR, NPDR without DME and STDR asthe dependent variables and serum adiponectin as the independentvariable (Fig. 5). Analysis revealed that adiponectin was positively

ations [n = 221] With microvascular complications [n = 266] p value

54.7 ± 11.1 b0.001136 (51.1) 0.37190.1 ± 10.0 0.03024.7 ± 4.5 b0.001132.0 ± 19.0 b0.00178.0 ± 12.0 0.985170.1 ± 65.0 b0.0019.0 ± 2.2 b0.0016.4 ± 6.2 b0.001198.0 ± 41.6 0.724144.2 0.91843.1 ± 10.6 0.171122.0 ± 36.1 0.31725.6 b0.0016.1 0.004

16 (7.2)182 (82.4) 0.190⁎⁎

23 (10.4)

crovascular complications and n = 221 for subjects with microvascular complications].



Fig. 2. Serum adiponectin levels in relation to the number of diabetic microvascularcomplications.

Fig. 4. Serum adiponectin levels in relation to the severity of diabetic retinopathy.


associated with NPDR without DME (OR: 1.82, 95% CI: 1.08–3.06,p = 0.024) and STDR (OR: 3.45, 95% CI: 1.04–11.39, p = 0.043)even after adjusting for age, gender, BMI, HbA1c, diabetes of dura-tion and systolic blood pressure. Similar analysis was done usingthe severity of nephropathy; however adiponectin was not associ-ated with the severity of nephropathy even in the unadjustedmodel.

The association of serum adiponectin with microvascular com-plications (presence of neuropathy and/or retinopathy and/ornephropathy) was analyzed using multiple logistic regression analy-sis. Logistic regression analysis revealed adiponectin to be associatedwith microvascular disease in the unadjusted model (OR: 1.55, 95%CI: 1.13–2.13, p = 0.006). The association persisted (OR: 1.55, 95%CI: 1.01–2.39, p = 0.047) even after adjusting for age, gender,BMI, HbA1c, duration of diabetes, serum cholesterol, triglycerides,hypertension and medication status (Table 2).

Fig. 3. Serum adiponectin levels in subjects with and


Discussion

The major findings of the study are: 1) With increasing number ofmicrovascular complications the levels of adiponectin increased in thestudy subjects and an increased adiponectin levels were associatedwith a significantly increasing odds of microvascular complicationseven after adjusting for several confounders; 2) adiponectin levelswere significantly higher in subjects with diabetic retinopathy anddiabetic neuropathy compared to their respective controls, whereasadiponectin levels did not differ significantly in subjects with andwithout nephropathy; and 3) when subjects with retinopathy weresegregated on the basis of severity, the levels of adiponectin increasedwith increasing severity of the disease and adiponectin levels werefound to be positively associated with the severity of the disease evenafter adjusting for confounders like age, gender, BMI, HbA1c, durationof diabetes, hypertension and medication status.

without diabetic microvascular complications.



Fig. 5. Association of serum adiponectin with the severity of diabetic retinopathy.

5R. Pradeepa et al. / Clinical Biochemistry xxx (2014) xxx–xxx

We have earlier reported that serum adiponectin levels weredecreased in type 2 diabetic subjects in general [23]. In this study wereport increased adiponectin levels in type 2 diabetic subjects with mi-crovascular complications compared to those without. This V-shapedassociation has been reported earlier by Habeeb et al. [24] in type 1diabetes, where the adiponectin level was significantly elevated inpatients with complications compared to those without as well as thecontrol group.

Yilmaz et al. [9] have reported decreasing levels of adiponectin withincreasing severity of the disease. However, Zietz et al. [10] have report-ed elevated levels of adiponectin in the serum in diabetic retinopathy.A Japanese study has also reported that serum adiponectin levels werepositively correlated with the severity of retinopathy which is in agree-ment with our results [25]. In type 1 diabetes, in subjects with retinop-athy, plasma adiponectin levels were found to be elevated in severalreports [26,27]. The reason for the increase in adiponectin levels indiabetic retinopathy and its association with the severity of retinopathyis not clear. It is possible that increased adiponectin might also lead toworsening of diabetic retinopathy although this is not in agreement

Table 2Multiple logistic regression analysis using microvascular complications as dependantvariable.

Variable Odds ratio[OR]

95% confidenceinterval [CI]

p value

Serum adiponectinUnadjusted 1.55 1.13–2.13 0.006Adjusted model [adjusted for age,gender, BMI, HbA1c, duration ofdiabetes, serum cholesterol, serumtriglycerides, hypertension andmedication status]

1.55 1.01–2.39 0.047

p b 0.05 is significant and marked in bold


with the proven beneficial effects of adiponectin. However, in the lightof the recent findings that some of the isoforms of adiponectin promoteinflammation [28], this might be a plausible explanation.

There are also other factors like duration of diabetes and uncon-trolled hyperglycemia that influence the progression to diabeticretinopathy [29]. However, our regression models showed a signif-icant association of adiponectin with diabetic retinopathy evenafter adjusting for duration of diabetes, HbA1C and several otherconfounders.

Several studies have shown increased levels of adiponectin indiabetic nephropathy as impaired clearance of adiponectin via therenal system might contribute to the increased circulating levels ofadiponectin as the kidney is an important site for the elimination ofadiponectin [13,30,31]. Another reason could be that a secondary resis-tance could have developed in the kidney to adiponectin [32]. In ourstudy, although adiponectin levels were increased in nephropathy, thedifference did not reach statistical significance. This may be becausethe number of study subjects with advanced nephropathy was smallin our study.

Adiponectin has been shown to play a role not only in angiopathybut also in neuropathy. Higher levels of adiponectin in serum havebeen shown to be associated with cardiac autonomic neuropathy andthe association was found to be independent of traditional and non-traditional risk factors [15]. However, Kato et al. [25] have shown thatadiponectin levels are not associated with neuropathy. As the cytokineexpression profile in neuropathy has been found to be predominantlypro-inflammatory with increasing levels of TNF-α and IL-6, the increasein adiponectinmight likely serve as an anti-inflammatorymechanism tocounteract the subclinical inflammation observed in neuropathy [33].

There are several limitations in the study. It is a cross-sectionaldesign which cannot determine the cause of the observed increasein adiponectin in retinopathy and neuropathy subjects and for this




prospective studies are clearly required. Secondly we could not assessthe relationship between adiponectin and stages of neuropathy.However, this is the first study to provide data on the association ofadiponectin levels with complications of diabetes in Asian Indian type2 diabetic subjects.

In summary, we report that in Asian Indians with type 2 diabetesserum adiponectin levels are associated with microvascular complica-tions and also with the severity of retinopathy.

Conflict of interest

The author(s) declare(s) that there is no conflict of interests regard-ing the publication of this paper.

Acknowledgment

We acknowledge gratefully the help of the epidemiological team forthe fieldwork, eye technicians for performing preliminary eye testingand retinal photography, technicians for performing biothesiometryand most importantly the subjects who participated in the study. Thisis the 133 study from the CURES. JS and KI acknowledge the fellowshipfrom CSIR-SRF.

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