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ScienceDirect www.sciencedirect.com Annales d’Endocrinologie 75 (2014) 200–205

Original article

Evaluation of the relationship between serum apelin levels and vitamin D and mean platelet volume in diabetic patients Évaluation de la relation entre les taux sériques d’apeline, de vitamine D et le volume moyen de plaquettes chez les patients diabétiques Muharrem Kiskac a,∗ , Mehmet Zorlu a , Mustafa Cakirca a , Cumali Karatoprak a , Sıdıka Kesgin b , Banu Büyükaydın a, Erdinc Yavuz c, Cuneyt Ardic c, Ahmet Adil Camli a, Mehmet Ali Cikrikcioglu a a b

Internal Medicine Clinic, Bezmialem Vakif University, Faculty of Medicine, 34093 Fatih, Istanbul, Turkey Department of Biochemisty, Bezmialem Vakif University, Faculty of Medicine, 34093 Fatih, Istanbul, Turkey c Family Care Center Rize, Turkey

Abstract Objectives. – It was reported that Vitamin D deficiency was associated with a greater risk of cardiometabolic diseases, obesity, impaired glucose tolerance and diabetes mellitus type 2, arterial hypertension, and dyslipidemia. Apelin is an adipocytokine suspected to have a role in skeletal muscle glucose utilization and glycemic regulation which may be a promising treatment modality for diabetes. It was recently reported that increased mean platelet volume (MPV) was emerging as an independent risk factor for thromboembolism, stroke, and myocardial infarction. In patients with diabetes, MPV was higher compared with the normal glycemic controls; in addition, it has been proposed that an increase in MPV may play a role in the micro- and macro-vascular complications related to diabetes. We postulated that deficiency in Vitamin D levels might be associated with higher MPV and lower serum apelin levels leading a further increase in insulin resistance in diabetic patients. So, we aimed to investigate Vitamin D levels, MPV and serum apelin levels in diabetic patients and their correlations between each other. Materials and method. – This is a cross-sectional study design. Seventy-eight patients with Diabetes Mellitus type 2, admitted to our outpatient clinic of internal medicine department at Bezmialem Vakif University, were included in our study. Forty-one patients were female; 37 patients were male. Serum apelin levels, fasting glucose levels, urea, creatinine, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting serum insulin level, HbA1c , free T3, free T4, TSH, vitamin D (25-OH Vitamin D) and complete blood counts were analyzed in all subjects. Results. – Each sex was analyzed separately. We found that a positive correlation existed between serum apelin levels and BMI in female patients. (r: 0.380, P: 0.014) There was also a significant positive correlation between MPV and HbA1c and fasting glucose levels and a negative correlation between MPV and PLT. (r: 0.377, P: 0.021; r: 0.395, P: 0.014; r: −0.401, P: 0.011; respectively) We failed to show a significant relationship between serum vitamin D levels, serum apelin levels and MPV in patients with diabetes mellitus type 2. Conclusion. – We failed to show an association between vitamin D, apelin and MPV higher volumes of which may have a role in cardiovascular complications related to diabetes by increasing platelet activation. © 2014 Published by Elsevier Masson SAS. Keywords: Diabetes mellitus; Apelin; Vitamin D; MPV

Résumé Objectifs. – Une carence en vitamine D a été associée à un risque accru de maladies cardiométaboliques, d’obésité, d’intolérance au glucose et de diabète de type 2, d’hypertension artérielle et de dyslipidémie. L’apéline est un adipocytokine suspecté d’avoir un rôle dans l’utilisation du glucose par le muscle squelettique et dans la régulation de la glycémie, ce qui peut être une modalité thérapeutique prometteuse pour le diabète. Il a été récemment rapporté que l’augmentation du volume moyen de plaquettes (VMP) était en train de



Corresponding author. E-mail addresses: dr [email protected] (M. Kiskac), [email protected] (M. Zorlu), [email protected] (M. Cakirca), [email protected] (C. Karatoprak), [email protected] (S. Kesgin), [email protected] (B. Büyükaydın), [email protected] (E. Yavuz), [email protected] (C. Ardic), [email protected] (A.A. Camli), [email protected] (M.A. Cikrikcioglu). http://dx.doi.org/10.1016/j.ando.2014.07.112 0003-4266/© 2014 Published by Elsevier Masson SAS.

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devenir un facteur de risque indépendant de maladie thromboembolique, d’accident vasculaire cérébral et d’infarctus du myocarde. Chez les patients diabétiques, le VPM est plus élevé par rapport aux contrôles glycémiques normaux ; en outre, il a été suggéré qu’une augmentation du VPM pouvait jouer un rôle dans les complications micro-et macro-vasculaires liées au diabète. Nous avons postulé qu’une carence en vitamine D pouvait être associée à une augmentation du VPM et à des taux sériques d’apeline plus faibles, induisant une nouvelle augmentation de la résistance à l’insuline chez les patients diabétiques. Ainsi, nous avons cherché à étudier les taux de vitamine D, le VPM et les niveaux sériques d’apéline chez les patients diabétiques de meme que leurs corrélations entre eux. Matériel et méthode. – Il s’agit d’une étude transversale. Parmi les patients, 78 atteints de diabète de type 2 admis en ambulatoire dans le service de médecine interne de l’hôpital universitaire Bezmialem Vakif ont été inclus dans notre étude. Parmi les patients, 41 étaient des femmes ; 37 patients étaient de sexe masculin. Les taux sériques d’apéline, la glycémie à jeun, l’urée, la créatinine, les triglycérides, le cholestérol total, le cholestérol LDL (LDL-C), les lipoprotéines de haute densité (HDL-C), le taux d’insuline à jeun, le taux d’HbA1c , de T3 libre, de T4 libre, de TSH, de vitamine D (25-OH vitamine D) et une numération globulaire complète ont été analysés chez tous les sujets. Résultats. – Chaque sexe a été analysé séparément. Nous avons constaté qu’une corrélation positive existait entre les taux sériques d’apéline et l’IMC chez les patients de sexe féminin. (r : 0,380, p : 0,014) Il existait aussi une corrélation positive significative entre les taux de glucose à jeun et ceux de HbA1c , ainsi que le VPM et une corrélation négative entre le volume moyne de plaquettes et leur comptage (r : 0,377, p : 0,021 ; r : 0,395, p : 0,014 ; r : −0,401, p : 0,011, respectivement). Nous ne sommes pas parvenus à montrer de relation significative entre les taux sériques de vitamine D, d’apéline et le VPM chez les patients atteints de diabète de type 2. Conclusion. – Nous n’avons pas réussi à montrer d’association entre vitamine D, apéline et VMP dont des volumes augmentés pourraient jouer un rôle dans les complications cardiovasculaires liées au diabète en augmentant l’activation plaquettaire. © 2014 Publié par Elsevier Masson SAS. Mots clés : Diabète sucré ; Apéline ; Vitamine D ; VMP

1. Introduction It is estimated that a billion people worldwide suffers from vitamin D deficiency [1–3]. According to recent data, there may be a connection between vitamin D levels and cardiometabolic diseases, obesity, impaired glucose tolerance and diabetes mellitus type 2, arterial hypertension, and dyslipidemia. Although the mechanisms are still unclear, vitamin D deficiency is associated with a greater risk of these pathological conditions [3–8]. Numerous studies investigated the relationship between vitamin D and insulin levels. Vitamin D receptors found in pancreatic ß-cells launched studies on the possible effects of calcitriol on regulation of insulin production [8,9]. Adipocytes secrete a wide range of molecules called adipocytokines which were suggested to have a role in the pathogenesis of metabolic syndrome [10]. Apelin is a member of this adipocytokine family. In a study with human and rat adipocytes, it was found that apelin was secreted mainly from adipocytes and up-regulated by insulin [11]. An acute intravenous injection of apelin in rats increases skeletal muscle glucose utilization and blood sugar decreases substantially. Therefore, apelin may be promising in the treatment of insulin resistance [12]. It was shown that increased Mean Platelet Volume (MPV) was associated with increased platelet activation [13]. Recently, increased MPV is emerging as an independent risk factor for thromboembolism, stroke, and myocardial infarction. In patients with diabetes, MPV was higher compared with the normal glycemic controls; in addition, it has been proposed that an increase in MPV may play a role in the micro- and macrovascular complications related to diabetes [14–16]. Because the relationship between Vitamin D, serum apelin levels and MPV with diabetes mellitus, insulin resistance and metabolic syndrome have been demonstrated in many studies, we thought that their relationship to each other in diabetic patients might give us new information. Our literature search

failed to find a study investigating the association between these three markers, Vitamin D, serum apelin levels and MPV in diabetic patients. We postulated that deficiency in Vitamin D levels might be associated with higher MPV and lower serum apelin levels leading a further increase in insulin resistance in diabetic patients. So, we aimed to investigate Vitamin D levels, MPV and serum apelin levels in diabetic patients and their correlations between each other. 2. Materials and method 2.1. Study group Seventy-eight patients with Diabetes Mellitus type 2 admitted to our outpatient clinic of internal medicine department at Bezmialem Vakif University were included in our study. An approval from Bezmialem Vakif University Ethics committee and written consents of all participants were obtained. This is a cross-sectional study design. Patients with malignancies, chronic renal failure, chronic hepatic failure, psychiatric diseases, coronary artery disease, cerebrovascular diseases, pregnancy, abnormalities in thyroid function tests and patients under insulin and vitamin D replacement therapy were excluded from the study. All volunteers underwent a thorough physical examination and their height, weight, were recorded. Weight and height were measured to the nearest kilogram and centimeter, respectively, and BMI (body mass index) was calculated as in the formula, BMI = weight/(height)2 . 2.2. Blood assay Serum of all participants was obtained from 10–12 hours of fasting venous blood samples taken between 08:00 and 08:30 hours and centrifuged at 3600 rpm for 10 minutes. Fasting

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glucose level, urea, creatinine, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting serum insulin level, HbA1c , free T3, free T4, TSH, vitamin D (25-OH Vitamin D) were analyzed in all subjects. Complete blood count (CBC) was performed with blood tubes with EDTA and without delay for each patient. Serum of all participants was stored at −80 ◦ C in Eppendorf tubes until the measurement of apelin levels. The measurement was performed in serum samples brought to room temperature with a Thermo Scientific Multiskan FC (USA) analyzer. Serum apelin levels were measured using a commercial enzyme immunoassay kit (Phoenix, USA) according to the manufacturer’s instructions. Samples were measured in duplicate, and the average was used in the data analysis.

2.3. Statistical analysis SPSS (Statistical Package for Social Sciences) for Windows 20.0 software was used to perform the statistical analysis of the data. The continuous variables were expressed as mean ± standard deviation. Continuous variables were compared between the two groups using Mann-Whitney U test. Student’s t-test was used to compare parametric variables between the patient and control groups and chi-square test was used for categorical variables. Bivariate correlation analyses were done by Spearman’s test. A P value < 0.05 was considered statistically significant.

Table 1 The comparison of anthropometric and biochemical characteristics of male and female patients. Females (n: 41) Mean ± SD Age (years) BMI (kg/m2 ) Vitamin D (ng/mL) MPV (fL) Apelin level (ng/mL) HbA1c (%) Fasting glucose (mg/dL) Total cholesterol (mg/dL) Triglyceride (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL)

Males (n: 37) Mean ± SD

P value

51.22 ± 9.40 33.53 ± 4.29 12.20 ± 7.58

49.41 ± 9.59 28.49 ± 3.52 23.86 ± 8.41

0.402 0.001 0.001

10.60 ± 1.02 0.850 ± 0.562

10.53 ± 0.71 0.805 ± 0.583

0.745 0.731

7.48 ± 1.63 161.48 ± 60.84

7.84 ± 2.07 158.89 ± 57.32

0.398 0.849

211.54 ± 46.16

199.78 ± 49.45

0.276

183.05 ± 83.95

213.00 ± 170.2

0.331

138.29 ± 46.05

125.76 ± 37.59

0.195

45.12 ± 13.48

40.27 ± 9.58

0.074

Mean ± SD: mean ± standard deviation; BMI: body mass index; MPV: mean platelet volume; HbA1c : glycated hemoglobin; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol.

60 50 40

Females

30

Males

20 10 0 Age (p:0.402) BMI (p

Evaluation of the relationship between serum apelin levels and vitamin D and mean platelet volume in diabetic patients.

It was reported that Vitamin D deficiency was associated with a greater risk of cardiometabolic diseases, obesity, impaired glucose tolerance and diab...
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