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Clinical Biochemistry 42 (2009) 1401–1406

Early predictors of microvascular complications in type 1 diabetic patients

Awatif M. Abd El-Maksoud a, Mohammed H. El Hefnawy b, Shaymaa M.M. Yahya c,⁎,Dina M. Seoudi d, Abdel-Rahman B. Abdel-Ghaffar d, Emad F. Eskander c,

Hanaa H. Ahmed c, Ibrahim H. Kamal d

a Clinical Nutrition Department, National Nutrition Institute, Cairo, Egyptb Pediatric Department, National Institute of Diabetes and Endocrinology, Cairo, Egypt

c Hormone Department, National Research Centre, Cairo, Egyptd Biochemistry Department, faculty of Science, Ain Shams University, Cairo Egypt

Received 15 April 2009; received in revised form 29 May 2009; accepted 4 June 2009Available 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 sensitivepredictors for the microvascular complications monitored by microalbuminuria concentration and glycemic control indices.© 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 5–10% 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-ing C peptide despite hyperglycemia [1].

There are numerous mechanisms whereby microvascularproblems can develop in patients with diabetes. Hyperglycemiacan cause increase in polyol pathway flux, increases in protein

⁎ Corresponding author. Fax: +202 33370931.E-mail address: [email protected] (S.M.M. Yahya).

0009-9120/$ - see front matter © 2009 The Canadian Society of Clinical Chemistsdoi:10.1016/j.clinbiochem.2009.06.008

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 riskfactor 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.

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http://dx.doi.org/10.1016/j.clinbiochem.2009.06.008

1402 A.M. Abd El-Maksoud et al. / Clinical Biochemistry 42 (2009) 1401–1406

over 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-α-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 μg/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 “areadipocytokines more predictive for microvascular complica-tions than low grade inflammatory markers? To achieve thisaim, 63 previously diagnosed type 1 diabetic subjects from the

out 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 asMean±standard deviation of mean (SDM) and the range isstated 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

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

Parameters Normoalbuminuric(n=30)

Microalbuminuric(n=33)

Age (years) 12.06±3.0 (5.5–17.5) 12.3±2.9 (6.0–16.0)Sex (M/F) (16/14) (19/14)Diabetic duration

(years)4.6±2.4 (1–14) 4.3±3.2 (0.5–12)

Family historyof diabetes

43.5% (+ve),56.5% (−ve)

55.2% (+ve),44.8% (−ve)

Daily insulin dose(units)

53.0±18.1 (20–105) 54.7±29.5 (20–180)

Weight (kg) 43.7±14.3 (13–72) 44.8±12.2 (24–74)Height (m) 1.44±0.13 (1.18–1.79) 1.45±0.13 (1.23–1.65)Body mass index

(kg/m2)20.4±4.3 (6.7–27.8) 20.8±4.1 (13.9–29.8)

Systolic blood pressure(mm Hg)

108.5±9.4 (90–130) 110.2±9.5 (90–140)

Diastolic bloodpressure (mm Hg)

71.0±8.9 (60–90) 71.0±8.2 (60–90)

Fasting bloodglucose (mg/dl)

178.0±68.3 (84.2–333.6) 191.0±78.2 (49.0–319.6)

Glycated hemoglobinA1c (%)

7.8±1.4 (5.6–10.9) 8.4±1.2 (5.4–11.7)

Total hemoglobin (g%) 10.8±1.0 (7.0–13.1) 10.5±1.4 (8.5–13)

Data are expressed as Mean±S.D., range is stated between parentheses.

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



Adiponectin (μg/mL) 20.7±6.7 (10.2–36.7) 25.8±9.9 ⁎ (14.2–58.2)Leptin (ng/mL) 18.8±18.2 (0.9–70.8) 10.4±8.6 ⁎ (0.7–36.5)Interlukein-6 (pg/mL) 0.96±0.74 (0.4–3.9) 2.0±3.2 (0.19–14.78)C-reactive protein (μg/mL) 2.8±2.1 (0.2–9.5) 3.9±3.3 (0.9–12.2)Adiponectin/leptin ratio 2.5±2.6 (0.29–11.33) 6.0±7.7 ⁎ (0.39–39.3)

Data are expressed as Mean±S.D., range is stated between parentheses.⁎ Pb0.05.

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

Parameters(Log-transformed)

Correlationcoefficient (r=)

P-value Significance

Age −0.13 0.305 Non significantDiabetic duration −0.089 0.492 Non significantDaily insulin dose 0.052 0.708 Non significant

1403A.M. Abd El-Maksoud et al. / Clinical Biochemistry 42 (2009) 1401–1406

were skewed so the data were log transformed to obtain a morenormally distributed data. The relationship between adiponec-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.



Microaluminuria(mg/gmcreatinine)

11.7±4.9(4–22.4)

85.9±137.0 ⁎⁎

(23.2–300.0)Creatinine in urine (g/L) 0.67±0.34 (0.2–1.9) 0.63±0.43 (0.2–2.1)Serum creatinine (mg/dL) 0.49±0.177 (0.1–0.9) 0.45±0.17 (0.1–0.8)Blood urea (mg/dL) 17.7±6.1 (7–30) 19.0±7.8 (9–39)

Data are expressed as Mean±S.D., range is stated between parentheses.⁎⁎ Pb0.01.

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 μg/mL vs 20.7 μg/mL). On the contrary, leptinshowed a significant decrease in microalbuminuric subjects(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

Weight 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 urea 0.102 0.483 Non significantSerum creatinine −0.193 0.132 Non significantLeptin 0.006 0.965 Non significantInterlukein-6 0.092 0.475 Non significantC-reactive protein 0.184 0.152 Non significant

Table 5Multiple regression analysis for log adiponectin in type 1 diabetic subjects.

Independentvariable

Β-regressioncoefficient

SE of regressioncoefficient

t- P-value

Intercept 0.640 0.365 1.750 0.085Log BMI 0.227 0.187 1.209 0.231Log FPG −0.200 0.102 0.723 0.473LogHBA1c 0.138 0.281 0.492 0.624Log microalbumin 0.200 0.042 2.006 0.05

BMI: body mass index; FPG: fasting plasma glucose; HBA1c: glycatedhemoglobin A1c.

Table 7Multiple regression analysis for log leptin in type 1 diabetic subjects.

Independentvariable



t- P-value

Intercept −2.111 3.145 −0.671 0.505Log BMI 0.705 0.575 1.225 0.226Log sBP 1.992 1.476 1.350 0.183Log FPG −0.539 0.290 −1.858 0.069LogHBA1c −0.911 0.785 −1.160 0.251Log CRP 0.280 0.162 0.222 0.089

BMI: body mass index; sBP: systolic blood pressure; FPG: fasting plasmaglucose; HBA1c: glycated hemoglobin A1c; CRP: C-reactive protein.


C-reactive protein (r=0.250, p= 0.05). Multiple regressionanalysis for leptin showed that body mass index, systolic bloodpressure, fasting plasma glucose, glycated hemoglobin A1c, andC-reactive protein were not independent predictors of leptin intype 1 diabetic subjects (Table 7).

Adiponectin to leptin ratio showed a strong significantpositive correlation with fasting plasma glucose (r=0.326,p= 0.009). It showed a significant positive correlation withglycated hemoglobin A1c (r=0.293, p= 0.02). Adiponectin toleptin ratio also showed a significant positive correlation withmicroalbuminuria (r=0.288, p= 0.022). Moreover, there was asignificant negative correlation between adiponectin/leptin ratioand urine creatinine (r=−0.255, p= 0.046) (Table 8). Multipleregression analysis for adiponectin/leptin showed that fastingplasma glucose, glycated hemoglobin A1c, microalbumin andurine creatinine were not independent predictors of adiponectin/leptin in type 1 diabetic subjects (Table 9).

Discussion

An interesting finding in our study is that plasma adiponectinconcentration was significantly raised in microalbuminuric type

Table 6Correlations between log leptin and measured parameters in type 1 diabeticsubjects.




Age −0.107 0.403 Non significantDiabetic duration 0.125 0.334 Non significantDaily insulin dose 0.103 0.453 Non significantWeight 0.138 0.282 Non significantHeight −0.124 0.332 Non significantBody mass index 0.297 0.018 SignificantSystolic blood pressure 0.263 0.042 SignificantDiastolic blood pressure 0.143 0.278 Non significantFasting blood glucose −0.299 0.017 SignificantGlycated hemoglobin A1c −0.257 0.042 SignificantTotal hemoglobin −0.201 0.114 Non significantMicroalbuminuria −0.212 0.095 Non significantUrine creatinine 0.202 0.115 Non significantBlood urea −0.126 0.384 Non significantSerum creatinine −0.152 0.238 Non significantAdiponectin 0.006 0.965 Non significantInterlukein-6 0.136 0.289 Non significantC-reactive protein 0.250 0.050 Significant

1 diabetic subjects as compared to normoalbuminuric type 1diabetic subjects. This finding disagrees with that of Saraheimoet al. [22] who found that no difference was observed betweensubjects with microalbuminuric and normoalbuminuric type 1diabetic subjects. Indeed, they found a significant differencebetween macroalbuminuric and both microalbuminuric andnormoalbuminuric subjects. Our observation may partially besupported by the finding of Risch et al. [23] who found anindependent negative association between glomerular filtrationrate (GFR), which is expected to be reduced in microalbumi-nuric subjects, and the serum concentrations of adiponectin.

As adiponectin in addition to leptin are proteins withrelatively low molecular weight, it can be assumed that reducedexcretory kidney function exerts an influence on the respectiveprotein concentrations [24]. The collagenous domain of theadiponectin molecule has four conserved lysines that can behydroxylated and glycosylated. Both hydroxylation andglycosylation are suggested to be critical for the threedimensional structure of the biologically active adiponectinmolecule. It is likely that glycosylation is one of the major post-translational modifications of adiponectin [25]. In diabeticpatients with constant hyperglycemia, the glycosylation process

Table 8Correlations between log adiponectin/leptin ratio and measured parameters intype 1 diabetic subjects.




Age 0.060 0.642 Non significantDiabetic duration −0.147 0.255 Non significantDaily insulin dose −0.079 0.566 Non significantWeight −0.022 0.864 Non significantHeight 0.173 0.174 Non significantBody mass index −0.236 0.062 Non significantSystolic blood pressure −0.250 0.054 Non significantDiastolic blood pressure −0.149 0.255 Non significantFasting blood glucose 0.326 0.009 SignificantGlycated hemoglobin A1c 0.293 0.020 SignificantTotal hemoglobin 0.143 0.262 Non significantMicroalbuminuria 0.288 0.022 SignificantUrine creatinine −0.255 0.046 SignificantBlood urea 0.152 0.293 Non significantSerum creatinine 0.084 0.517 Non significantInterlukein-6 −0.099 0.438 Non significantCRP −0.179 0.165 Non significant

Table 9Multiple regression analysis for log adiponectin/leptin ratio in type 1 diabeticsubjects.

Independentvariable



t- P-value

Intercept −1.849 0.857 −2.157 0.035Log FPG 0.531 0.315 1.688 0.97LogHBA1c 0.885 0.839 1.055 0.296Log microalbumin 0.244 0.127 1.919 0.06Log urine creatinine −0.144 0.153 −0.942 0.350

FPG: fasting plasma glucose; HBA1c: glycated hemoglobin A1c.

1405A.M. Abd El-Maksoud et al. / Clinical Biochemistry 42 (2009) 1401–1406

is probably altered, and this could lead to an altered adiponectinfunction. Consequently, a modified adiponectin molecule couldlead to a diminished negative feed back, a mechanism that is anessential part of hormonal system, and thus to increaseadiponectin concentrations in diabetes [22]. One possibilitycould be that the state of microalbuminuria is accompanied by acertain degree of renal insufficiency that may further stimulateadiponectin production or alternatively leads to a defect in theclearance of adiponectin.

Saraheimo et al. [22] speculated that adiponectin itself mayhave a role in mitigating the micro and macrovascular burden indiabetic nephropathy. In our study, the situation may be similar,even if our subjects are not nephropathics but microalbumi-nuric, since the first clinical evidence is an increase in urinaryalbumin excretion (microalbuminuria), which may develop intoovert nephropathy (proteinuria) [26]. Huypens et al. [27] havefound that the two adiponectin receptors, R1 and R2, areexpressed in rat beta cells where they stimulate the AMP-activated protein kinase. Building on this finding we maypostulate that there is a downregulation of adiponectin receptorswhich may reset serum adiponectin concentration to a higherlevel.

In this study, we observed a positive correlation betweenadiponectin and microalbuminuria concentration in type 1diabetic subjects. This finding is in accordance with Saraheimoet al. [22] and Fujita et al. [28] who found a positive correlationbetween adiponectin and albumin excretion rate (AER) in type1 diabetic subjects. This unexpected positive association may bean adaptive mechanism by which the oxidative stress, which ispathophysiologically associated with diabetes and renal dys-function [29], may be counteracted. Moreover, Fujita et al. [28]found that adiponectin elevation in diabetic patients may be aphysiological response to avoid renal tubular injury and toprevent the infiltration of inflammatory cell into the tubuloin-terstitial area which is a hall mark of diabetic nephropathy thatmay be developed if further complications occur.

In this study, there was a significant decrease in leptinconcentrations of microalbuminuric type 1 diabetics ascompared to that of normoalbuminuric type 1 diabetic subjects.However there were no significant differences in inflammatorymarkers between microalbuminuric and normoalbuminuric type1 diabetic subjects. For a cell type to respond to leptin, leptinreceptors must be present in the plasma membrane. Two maintypes of leptin receptors also referred to as Ob receptors (Ob-R),have been identified [30]. The type with a long intracellular

domain (Ob-RL or Ob-Rb) which is the signaling form, elicitsprotein phosphorylation. The type with a short intracellulardomain (Ob-RS or Ob-Ra) may possess a transport function,allowing leptin to transverse a capillary such as the blood brainbarrier. Both types of receptors are expressed in humanendothelial cells as confirmed by Sierra-Honigmann et al.[12]. The order of magnitude of stimulation of angiogenesis byleptin is similar to that included by vascular endothelial growthfactor. So, if we assumed that leptin is involved in thepathogenesis of nephropathy, one may speculate that thedecreased level of leptin in microalbuminuric patients is anadaptive mechanism to counteract the process of angiogenesis.This decrease may be a direct effect mediated by the increasedOb-RL receptors or an indirect effect mediated by the increasedOb-RS.

Another explanation for the decreased levels of leptin in type1 diabetic subjects was introduced by Kratzsch et al. [31] whostated that metabolic decompensation in children with newonset T1DM is associated with dramatic changes of the leptinaxis; serum levels of soluble leptin receptors (sOB-R) areelevated and those of leptin reduced. This explanation maysupport our results in the current study and may introduce areason for the decreased leptin level in type 1 diabetic subjects.The molar excess of sOB-R over leptin in this condition maycontribute to leptin insensitivity. Upregulation of the solubleleptin receptor appears to be a basic mechanism to compensatefor intracellular substrate deficiency and energy-deprivationstate. The pathophysiological regulation and the mechanism ofthis shedding process are not completely understood. A possibleexplanation for the increase of sOB-R observed in type 1diabetic subjects may be the induction of the protein kinase C(PKC) activity in the diabetic state. PKC can induce Adisintegrin and metalloprotease (ADAM) 17 [32], which isable to shed the extracellular domain of cytokine-like hormonereceptors, such as the growth hormone-receptor and the OB-R,leading to increased levels of the soluble receptor. The fact thatdeficiency of substrates for the energy supply, such as lack ofintracellular glucose in T1DM, leads to increased levels ofcirculating sOB-R is in agreement with previous data showingthe same effect in conditions with weight loss, malnutrition,insulin treatment of T1DM with poor glycemic control, ornephrotic syndrome [33].

Also, there was a significant positive correlation betweenleptin and high sensitive C-reactive protein (hsCRP). Thisfinding is in accordance with that of Nishikawa et al. [34] whoreported that leptin correlates positively with hsCRP in vivo andoxidative stress in vitro and hence leptin might be related to pro-inflammatory status, which might provide a common patho-genic mechanism that contributes to several complicationsobserved in diabetic subjects [35].

Huypens [36] has postulated that leptin and adiponectin areinversely regulated in vivo, but not in vitro, suggesting that theinverse relationship is mediated via indirect mechanisms.According to the previous assumption, we can conclude thatadiponectin/leptin ratio may be used as a better marker formicrovascular complications than adiponectin or leptin alone.This was relevant in our study, as adiponectin to leptin ratio was


significantly elevated in microalbuminuric type 1 diabeticsubjects as compared to normoalbuminuric type 1 diabetics.Besides, adiponectin to leptin ratio showed a significant strongpositive correlation with fasting plasma glucose and glycatedhemoglobin HbA1c, which are both two important determinantsof the hyperglycemic state in diabetes. Also, it showed asignificant positive correlation with microalbuminuria concen-tration which is an early predictor of microvascular complica-tions. It also showed a negative correlation with urine creatinineconcentrations. Thus, adiponectin/leptin ratio was correlatedpositively with the microalbuminuria concentration and diabeticcontrol indices.

It can be suggested from this study that adiponectin andleptin are more predictive for microvascular complications thanlow grade inflammatory markers. Besides, we concluded thatthe adiponectin/leptin ratio may be used as a better marker formicrovascular complications than adiponectin or leptin alone,as the adiponectin/leptin ratio was correlated positively with themicroalbuminuria concentration and diabetic control indices.Hence, we deduced that adiponectin to leptin ratio may be usedas a good predictor for the renal insufficiency.

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