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Annales d'Endocrinologie
Volume 75, n° 4
pages 200-205 (septembre 2014)
Doi : 10.1016/j.ando.2014.07.112
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 Internal Medicine Clinic, Bezmialem Vakif University, Faculty of Medicine, 34093 Fatih, Istanbul, Turkey 
b Department of Biochemisty, Bezmialem Vakif University, Faculty of Medicine, 34093 Fatih, Istanbul, Turkey 
c Family Care Center Rize, Turkey 

Corresponding author.
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.

The full text of this article is available in PDF format.
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 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.

The full text of this article is available in PDF format.

Keywords : Diabetes mellitus, Apelin, Vitamin D, MPV

Mots clés : Diabète sucré, Apéline, Vitamine D, VMP


Introduction

It is estimated that a billion people worldwide suffers from vitamin D deficiency [1, 2, 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, 4, 5, 6, 7, 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 macro-vascular complications related to diabetes [14, 15, 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.

Materials and method
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.

Blood assay

Serum of all participants was obtained from 10–12hours of fasting venous blood samples taken between 08:00 and 08:30hours and centrifuged at 3600rpm for 10minutes. Fasting 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.

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.

Results

Forty-one patients were female; 37 patients were male. There was a significant difference between male and female patients in terms of BMI and vitamin D levels. In female group, BMI was significantly higher while vitamin D levels were significantly lower compared with the male group. Two different sex groups were similar in terms of age, serum apelin levels, MPV, fasting glucose levels, HbA1c , triglyceride, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) levels (Table 1, Fig. 1, Fig. 2). Because of the difference in BMI and vitamin D levels between two sexes, we carried out our analysis separately in each sex group.



Fig. 1


Fig. 1. 

The comparison of age, BMI and vitamin D levels in females and males. BMI: body mass index, VitD: vitamin D.

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Fig. 2


Fig. 2. 

The comparison of MPV and Apelin levels in females and males. MPV: mean platelet volume.

Zoom

In our laboratory, a 25-OH vitamin D level of 0–9.9ng/mL is considered as serious deficiency, levels from 10 to 23.9ng/mL are considered as moderate deficiency, levels between 24 and 80ng/mL are considered as optimal and levels higher than 81ng/mL are considered as possible toxicity. In the female group, mean vitamin D level was 12.20±7:58ng/mL. We divided these patients into two groups: 23 women with serious vitamin D deficiency (vitamin D levels were lower than 10ng/mL) and 18 women with a vitamin D level higher than 10ng/mL. In the male group, mean vitamin D level was 28.49±3.52ng/mL. We also divided these patients into two groups: 20 patients with vitamin D deficiency (vitamin D level lower than 24ng/mL) and 17 patients without vitamin D deficiency. We compared these same sex groups with each other.

In females, two groups did not differ in terms of age, BMI, serum apelin levels, HbA1c , fasting glucose level, triglyceride, total cholesterol, HDL-C, LDL-C, white blood cell count (WBC), hemoglobin, platelet count (PLT) and MPV (Table 2). In males, groups were also similar when compared with the same parameters (Table 3).

The correlations between serum apelin levels, vitamin D levels and MPV and anthropometric, biochemical and hematologic characteristics of patients were also studied. We found that a positive correlation existed between serum apelin levels and BMI in female patients. (r : 0.380, P : 0.014) (Table 4). 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) (Table 5).

Discussion

In this study, we evaluated serum apelin, MPV and vitamin D levels in patients with diabetes mellitus type 2. We also researched the correlations between these markers and anthropometric and metabolic characteristics of the patients in similar groups. In female group, patients were more overweight than male group and vitamin D deficiency was more remarkable. Previous studies have shown that vitamin D deficiency was more frequent in females in adult age. A reason for this may be a higher amount of time spent indoors by females which may also lead to an underexposure to sunlight and a higher risk for vitamin D deficiency [17, 18].

Vitamin D subanalysis between groups in male and female patients showed no difference in terms of apelin and MPV. Higher apelin levels were detected in female patients with higher BMI. In patients with higher fasting glucose levels and HbA1c , higher levels of MPV and lower platelet counts were detected.

Vitamin D has an important role in glucose homeostasis. It improves β cell function and insulin sensitivity of the target cells. There is a complicated pathogenetic process between vitamin D deficiency and insulin resistance. Along with immunoregulatory dysfunction and inflammation related changes, inherited gene polymorphisms in terms of vitamin D binding protein, vitamin D receptor and CYP1 alpha gene have been implicated [19, 20]. In vitamin D deficiency, hypocalcemia can lower insulin secretion in β cell and also elevating PTH reduces glucose uptake by liver and adipose tissue [21].

Vitamin D deficiency is an important problem in obesity. The storage of vitamin D in adipose tissue increase PTH levels. An association between low vitamin D levels and metabolic syndrome has been reported in several studies [22]. Adipose tissue, acting as a metabolically responsive endocrine organ, secretes several adipokines. An increase in adipose tissue has been found to be related witg hyperlipidemia, insulin resistance, type 2 diabetes and cardiovascular diseases. Changes in the amount of adipokines secreted by adipose tissue were thought to play a role in pathogenesis of these diseases [23]. We failed to identify any study concerning vitamin D, apelin and MPV in this regard.

In our study, we found a positive correlation between serum apelin levels and BMI. Similarly, Kralisch et al. reported that serum apelin levels increased in obesity, insulin resistance and hyperinsulinemia [24]. Boucher et al. demonstrated that insulin was in direct control of apelin gene expression in adipocytes of obese patients and also the insulin and apelin levels significantly increased in obese patients [25].

As vitamin D deficiency was reported to be associated with metabolic syndrome, obesity and insulin resistance, as mentioned above, we considered that a possible relationship may exist between vitamin D and serum apelin levels. However, we failed to show such a relationship between vitamin D and apelin levels in male and female patients. Future larger studies on this matter may shed more light to the existence of this relationship.

We also found a significant positive correlation between MPV and HbA1c and fasting glucose levels in female patients group. This finding was in coherent with previous studies which reported that MPV was higher in diabetic patients 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 [14, 15, 16]. Therefore, we postulated that there may be a relationship between MPV and serum apelin and vitamin D levels. Our results also did not show a significant relationship among these markers. So, our findings suggested that serum apelin and vitamin D levels did not correlate with MPV and as a result did not affect thrombocyte activation due to high MPV. An important restriction of our study was the small sample size which was even smaller after sex separation. Further larger studies should be performed to confirm these results.

Conclusion

We failed to show an association between vitamin D, apelin and MPV which higher volumes may have a role in cardiovascular complications related to diabetes by increasing platelet activation. Further larger studies are needed to confirm these findings.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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