Early predictors of microvascular complications in type 1 diabetic patients

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  • mH.A, Ib

    tionof D

    Hormone Department, National Research Centre, Cairo, Egypt

    predictors for the microvascular complications monitored by microalbuminuria concentration and glycemic control indices.

    Available online at www.sciencedirect.com

    (200 2009 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

    Keywords: Adipocytokines; Inflammatory markers; Microalbuminuria; Glycemic control indices; Diabetic complications

    Introduction

    Type 1 diabetes (T1D) accounts for only about 510% of allcases of diabetes [1]; however, its incidence continues toincrease worldwide and it has serious short-term and long-termcomplications. T1D is characterized by the development of astate of complete insulin deficiency. In its fully developed form,patients will, if deprived of insulin, develop ketoacidosis, coma,and death. Biochemical testing reveals the absence of circulat-

    kinase C (PKC) isoform activity, and production of reactiveoxygen species and advanced glycation end products (AGE) [2].These pathways can lead to endothelial dysfunction, decreasedproduction of endogenous vasodilators such as nitric oxide(NO), release of endogenous vasoconstrictors, for exampleendothelin-1 (ET-1) or angiotensin II, release of growth factorssuch as vascular endothelial growth factor (VEGF) by endo-thelial cells, and production of pro-inflammatory cytokines bymacrophages [3]. Microalbuminuria is recognized as a riskAvailable online 24 June 2009

    Abstract

    Objectives: To investigate the possibility of depending on adiponectin and leptin as early predictors of microvascular complications in type 1diabetic subjects.

    Design and methods: We studied 63 type 1 diabetic subjects from the National Institute of Diabetes (30 normoalbuminuric and 33microalbuminuric). Clinical, demographic characteristics and kidney function tests were monitored. Plasma levels of adiponectin, leptin,interlukein-6 (IL-6), and the high sensitive C-reactive protein (CRP) were measured in these subjects.

    Results:Microalbuminuric subjects showed a significant elevation in adiponectin levels and a significant decrease in leptin levels as comparedto normoalbuminuric subjects. Adiponectin showed a significant positive correlation with microalbuminuria concentrations while leptin showed asignificant negative correlation with both fasting blood glucose and glycated hemoglobin A1c.

    Conclusion: The results of this study introduced the possibility of depending on adiponectin and leptin as early, reliable, and sensitived Biochemistry Department, faculty of Science, Ain Shams University, Cairo Egypt

    Received 15 April 2009; received in revised form 29 May 2009; accepted 4 June 2009Early predictors of microvascular co

    Awatif M. Abd El-Maksoud a, MohammedDina M. Seoudi d, Abdel-Rahman B.

    Hanaa H. Ahmed c

    a Clinical Nutrition Department, Nab Pediatric Department, National Institute

    c

    Clinical Biochemistry 42ing C peptide despite hyperglycemia [1].There are numerous mechanisms whereby microvascular

    problems can develop in patients with diabetes. Hyperglycemiacan cause increase in polyol pathway flux, increases in protein

    Corresponding author. Fax: +202 33370931.E-mail address: yahshay10@yahoo.com (S.M.M. Yahya).

    0009-9120/$ - see front matter 2009 The Canadian Society of Clinical Chemistsdoi:10.1016/j.clinbiochem.2009.06.008plications in type 1 diabetic patients

    El Hefnawy b, Shaymaa M.M. Yahya c,,bdel-Ghaffar d, Emad F. Eskander c,rahim H. Kamal d

    al Nutrition Institute, Cairo, Egyptiabetes and Endocrinology, Cairo, Egypt

    9) 14011406factor for increased mortality and renal dysfunction in T1D.Risk factors for development of nephropathy include positivefamily history, male sex, poor glycemic control, hypertension,smoking and the presence of retinopathy and coronary arterydisease [4].

    A large amount of adiponectin flows with the blood streamand, therefore, comes into contact with the vascular walls all

    . Published by Elsevier Inc. All rights reserved.

  • al Bover the body. Since adiponectin has the ability to bindsubendothelial collagens, endothelial injury may induceadiponectin for entering into the subendothelial space throughbinding to these collagens [5]. Adiponectin possesses anti-inflammatory effects [6], as adiponectin dose dependentlysuppresses TNF--stimulated adherence of monocytes tocultured human endothelial cells [7]. Regarding to the relationbetween adiponectin and kidney, Iwashima et al. [8] declaredthat renal function is a significant regulator of adiponectin whencategorized by chronic kidney disease stage.

    Leptin (from the Greek word leptos meaning thin) wasidentified by positional cloning in 1993 [9] as a key molecule inthe regulation of body weight and energy balance. Leptin, a16 kDa non-glycosylated polypeptide product of the obese (ob)gene, is an adipocyte-derived hormone which has long beenrecognized as a key factor in regulating a wide range ofbiological responses including energy homeostasis [10],neuroendocrine function [11], angiogenesis[12], bone forma-tion [13] and reproduction [14]. A growing body of evidenceindicates that leptin acts as a pro-inflammatory cytokine inimmune responses. Although pro-inflammatory factors arecritical mediators of host defense mechanisms, these cytokinescan negatively associate with the development of autoimmunediseases. Leptin has also been shown to enhance immunereactions in autoimmune diseases that are commonly associatedwith inflammatory responses [15]. The kidney has been shownto express mRNA for the full-length Ob-Rb leptin receptor,suggesting that leptin may exert functional effects in this organ[16]. Leptin acts on the renal tubules to promote natriuresis anddiuresis. Acute infusion of human leptin (0.3 to 30 g/min) intoa renal artery in anesthetized rats produced an ipsilateralincrease in sodium excretion and urine volume withoutsignificant effects on renal blood flow or glomerular filtrationrate [17].

    Prevention of long-term chronic complications has nowbecome one of the main goals of modern treatment in T1D inchildren and adolescents. Because early diagnosis and treatmentmay prevent the complications, new tools for an early detectionare needed. The inflammatory process seems to play animportant role in the development of both diabetes and its latecomplications. There is good evidence that inflammatorymarkers could be novel risk factor of diabetes. Adipose tissuederived pro-inflammatory cytokines may play a key role in thecombined insulin resistance syndrome and endothelial dysfunc-tion state, of which microalbuminuria seems to be an integratedmarker. In the present study, we aimed to investigate thepossibility of depending on adipocytokines, adiponectin andleptin as early and reliable predictors of microvascularcomplications, monitored by estimating the microalbuminuriaand diabetic control indices in type 1 diabetic subjects (childrenand adolescents). Also, we aimed in this study to explore therelations between these adipocytokines and low grade inflam-matory markers (CRP and IL-6) and different diabetic controlindices. Besides, this study tried to answer the question are

    1402 A.M. Abd El-Maksoud et al. / Clinicadipocytokines more predictive for microvascular complica-tions than low grade inflammatory markers? To achieve thisaim, 63 previously diagnosed type 1 diabetic subjects from theout patient clinic of the National Institute of Diabetes andEndocrinology, Cairo, Egypt were included in this study.

    Design and methods

    Patients

    This study included 63 previously diagnosed type 1 diabeticsubjects from the out patient clinic of the National Institute ofDiabetes and Endocrinology, Cairo, Egypt. Their age rangedfrom 5 to 17.5 years. Subjects were age and sex matched toexclude the age and sex effects. All type 1 diabetic patients metthe criteria of American Diabetes Association (ADA) for type 1diabetes [18]. None of type 1 diabetic subjects were receivingany medications other than insulin. They were furthersubdivided into two groups, normoalbuminuric and micro-albuminuric, according to microalbuminuria in the fresh urinesamples. Subjects having microalbuminuria concentrationlesser than 23.0 mg/g creatinine (2.0 mg/mmol creatinine)were considered normoalbuminuric whereas subjects havingmicoalbuminuria concentration equal to 23.0 mg/g creatinine(2.0 mg/mmol creatinine) and up to 300 mg/g creatinine wereconsidered microalbuminuric [19]. None of them was com-plaining of any chronic or acute illness. All patients weresubjected to full history including age, sex, diabetic durationand treatment. Weight, height monitoring, clinical examination,routine investigation including complete blood picture andurine analysis with culture and sensitivity were done. Writteninformed consent was obtained from the parents and this studywas approved by the Ethics Committee of the NationalResearch Centre and by that of the National Organization forTeaching Hospitals and Institutes.

    Preparation of samples and biochemical analyses

    Blood samples were drawn in the morning after an overnightfast. Morning urine samples were collected. Fasting plasmaglucose, blood urea, serum and urine creatinine, Glycatedhemoglobin A1c were determined according to standardprocedures. Microalbuminuria was determined by a turbidi-metric method according to Cambiaso et al. [20]. Plasmaadiponectin concentration was determined by an ELISA Kitprovided from Linco (USA). Plasma leptin was determined bythe ELISA kit provided by Diagnostic System Laboratories(USA). IL-6 was determined by the ELISA kit provided byEuroclone (Italy). CRP was determined by the ELISA kitprovided by Diagnostic System Laboratories (USA).

    Statistical analysis

    The data were analyzed using version 11.0 of the computer-based statistical package of Statistical Product and ServiceSolutions (SPSS, 2001) [21]. All the data are expressed asMeanstandard deviation of mean (SDM) and the range is

    iochemistry 42 (2009) 14011406stated between parentheses. The comparisons between the studygroups were done using the Student t-test with the aid ofLevens's test for the equality of variance. Some parameters

  • microalbuminuric subjects in plasma creatinine and bloodurea (Table 2).

    Microalbuminuric type 1 diabetic subjects showed asignificant increase in adiponectin as compared to normoalbu-minuric (25.8 g/mL vs 20.7 g/mL). On the contrary, leptinshowed a significant decrease in microalbuminuric subjects

    Table 1Clinical and demographic characteristics for normoalbuminuric and micro-albuminuric type 1 diabetic subjects.

    Parameters Normoalbuminuric(n=30)

    Microalbuminuric(n=33)

    Age (years) 12.063.0 (5.517.5) 12.32.9 (6.016.0)Sex (M/F) (16/14) (19/14)Diabetic duration(years)

    4.62.4 (114) 4.33.2 (0.512)

    Family historyof diabetes

    43.5% (+ve),56.5% (ve)

    55.2% (+ve),44.8% (ve)

    Table 3Adipocytokines and inflammatory markers for normoalbuminuric andmicroalbuminuric type 1 diabetic subjects.

    Parameters Normoalbuminuric(n=30)

    Microalbuminuric(n=33)

    Adiponectin (g/mL) 20.76.7 (10.236.7) 25.89.9 (14.258.2)Leptin (ng/mL) 18.818.2 (0.970.8) 10.48.6 (0.736.5)Interlukein-6 (pg/mL) 0.960.74 (0.43.9) 2.03.2 (0.1914.78)C-reactive protein (g/mL) 2.82.1 (0.29.5) 3.93.3 (0.912.2)Adiponectin/leptin ratio 2.52.6 (0.2911.33) 6.07.7 (0.3939.3)

    Data are expressed as MeanS.D., range is stated between parentheses. Pb0.05.

    1403A.M. Abd El-Maksoud et al. / Clinical Biochemistry 42 (2009) 14011406were skewed so the data were log transformed to obtain a morenormally distributed data. The relationship between adiponec-

    Daily insulin dose(units)

    53.018.1 (20105) 54.729.5 (20180)

    Weight (kg) 43.714.3 (1372) 44.812.2 (2474)Height (m) 1.440.13 (1.181.79) 1.450.13 (1.231.65)Body mass index(kg/m2)

    20.44.3 (6.727.8) 20.84.1 (13.929.8)

    Systolic blood pressure(mm Hg)

    108.59.4 (90130) 110.29.5 (90140)

    Diastolic bloodpressure (mm Hg)

    71.08.9 (6090) 71.08.2 (6090)

    Fasting bloodglucose (mg/dl)

    178.068.3 (84.2333.6) 191.078.2 (49.0319.6)

    Glycated hemoglobinA1c (%)

    7.81.4 (5.610.9) 8.41.2 (5.411.7)

    Total hemoglobin (g%) 10.81.0 (7.013.1) 10.51.4 (8.513)

    Data are expressed as MeanS.D., range is stated between parentheses.tin, leptin, adiponectin/leptin ratio, and the different measuredparameters was done using the bivariate correlation by the useof Pearson correlation coefficient. Moreover, multiple regres-sion analysis was applied to test the independent relation ofadiponectin, leptin, and adiponectin/leptin ratio to the sig-nificantly correlated parameters. A P-value of b0.05 wasconsidered significant.

    Results

    There were no significant differences in age, diabeticduration, daily insulin dose, weight, height, BMI, systolic anddiastolic blood pressure, fasting blood glucose, total andglycated hemoglobin between normoalbuminuric and micro-albuminuric subjects as shown in Table (1). Also, there wereno significant differences between normoalbuminuric and

    Table 2Body organ tests for normoalbuminuric and microalbuminuric type 1 diabeticsubjects.

    Parameters Normoalbuminuric(n=30)

    Microalbuminuric(n=33)

    Microaluminuria(mg/gmcreatinine)

    11.74.9(422.4)

    85.9137.0

    (23.2300.0)Creatinine in urine (g/L) 0.670.34 (0.21.9) 0.630.43 (0.22.1)Serum creatinine (mg/dL) 0.490.177 (0.10.9) 0.450.17 (0.10.8)Blood urea (mg/dL) 17.76.1 (730) 19.07.8 (939)

    Data are expressed as MeanS.D., range is stated between parentheses. Pb0.01.(10.4 ng/mL vs 18.8 ng/mL) when compared to normoalbumi-nuric subjects. On the other hand, neither interlukein-6 nor C-reactive protein showed significant differences (Table 3).

    Adiponectin showed a positive correlation with microalbu-minuria concentration (r=0.269, p= 0.033) (Table 4). Multipleregression analysis for adiponectin showed that only micro-albuminuria were an independent predictor of adiponectin intype 1 diabetic subjects (Table 5). As shown in Table 6, leptinshowed a significant positive correlation with BMI (r=0.297,p= 0.018). Also, there was a significant positive correlationbetween leptin and systolic blood pressure (r=0.263,p= 0.042). Leptin also showed a negative correlation withfasting blood glucose (r=0.299, p= 0.017). Besides, therewas a significant negative correlation between leptin andglycated hemoglobin A1c (r=0.257, p= 0.042). In addition,there was a significant positive correlation between leptin and

    Table 4Correlations between log adiponectin and measured parameters in type 1diabetic subjects.

    Parameters(Log-transformed)

    Correlationcoefficient (r=)

    P-value SignificanceAge 0.13 0.305 Non significantDiabetic duration 0.089 0.492 Non significantDaily insulin dose 0.052 0.708 Non significantWeight 0.036 0.778 Non significantHeight 0.113 0.378 Non significantBody mass index 0.142 0.267 Non significantSystolic blood pressure 0.006 0.964 Non significantDiastolic blood pressure 0.039 0.770 Non significantFasting blood glucose 0.132 0.301 Non significantGlycated hemoglobin A1c 0.151 0.236 Non significantTotal hemoglobin 0.148 0.248 Non significantMicroalbuminuria 0.269 0.033 SignificantUrine creatinine 0.206 0.109 Non significantBlood ur...

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