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ScienceDirect www.sciencedirect.com Annales d’Endocrinologie 75 (2014) 206–212
Original article
Correlations between serum levels of 25-hydroxyvitamin D and carotid atherosclerosis in patients with type 2 diabetes in Shanghai Corrélations entre taux sériques de 25-hydroxyvitamine D et athérosclérose carotidienne chez les patients atteints de diabète de type 2 à Shanghai Rui-hua Chen a , Xiao-zhen Jiang a,∗ , Quan Jiang b , Zhe Gu a , Pei-li Gu a , Bin Zhou a , Zhen-hong Zhu a , Lin-yan Xu a , Yu-feng Zou a a
Department of endocrinology, Pudong New Area People’s Hospital, 490, South Chuan Huan Road, Shanghai, China b Department of ultrasonography, Shanghai Pudong New Area People’s Hospital, Shanghai, China
Abstract Objective. – To explore the potential association between the serum levels of 25-hydroxyvitamin D [25(OH)D] and carotid atherosclerosis in patients with type 2 diabetes. Material and methods. – Three hundred and fifty patients with type 2 diabetes were enrolled in this study in Shanghai, China. B-mode ultrasound was used to detect carotid plaques as indicators of atherosclerosis and measure carotid artery intima-media wall thickness (C-IMT) at two sites of carotid artery. Subjects were divided into group A (patients with carotid plaques) and group B (patients without carotid plaques) and be assessed clinically. Serum levels of 25(OH)D and other clinical parameters were measured. Multivariate logistic regression was performed to find predictors of carotid atherosclerosis in the entire group. Results. – The levels of serum 25(OH)D were lower in group A than in group B[19.60 (13.30–25.73) vs 23.19 (18.10–30.06) ng/ml, P < 0.001]. The C-IMT levels [(1.00 ± 0.17 vs 0.88 ± 0.20) mm, Ptrend < 0.001] and proportion of people with carotid plaques(44/88 vs 20/87, Ptrend < 0.001) in the lowest quartile of 25(OH)D were higher than in the highest quartile. Vitamin D concentrations were inversely associated with HbA1c in women(r = −0.194, P = 0.006), and C-IMT in men(r = −0.409, P < 0.001). Logistic regression analysis showed age, male sex, current smoke, history of hypertension, SBP, LDL-C and lg[25(OH)D] (OR: 0.924, 95%CI: 0.893–0.955, P < 0.001) were independently associated with the presence of carotid plaques in T2DM. Conclusions. – Serum vitamin D level is significantly and independently associated with carotid atherosclerosis in patients with T2DM in Shanghai, China. © 2014 Published by Elsevier Masson SAS. Keywords: Diabetes mellitus type 2; 25-hydroxyvitamin D; Atherosclerosis; Carotid intima-media thickness
Résumé Objectif. – Explorer l’association potentielle entre les taux sériques de 25-hydroxyvitamine D [25(OH)D] et l’athérosclérose carotidienne chez les patients atteints de diabète de type 2. Matériel et méthodes. – Trois cent cinquante patients atteints de diabète de type 2 ont été inclus dans cette étude menée à Shanghai, en Chine. L’échographie en mode B a été utilisée pour détecter les plaques carotidiennes indiquant une athérosclérose et mesurer l’épaisseur de la paroi intima-média carotidienne (C-IMT) en deux endroits de l’artère carotide. Les patients ont été divisés en groupe A (patients atteints de plaques carotidiennes) et groupe B (patients sans plaques carotidiennes) et évalués cliniquement. Les niveaux sérologiques de 25 (OH) D et d’autres paramètres cliniques ont été mesurés. Une régression logistique multivariée a été effectuée pour trouver des prédicateurs de l’athérosclérose carotidienne dans l’ensemble du groupe. Résultats. – Les taux sériques de 25(OH)D étaient plus faibles dans le groupe A que dans le groupe B [19,60 (13,30 à 25,73) vs 23,19 (18,10 à 30,06) ng/mL, p < 0,001]. Les niveaux C-IMT [(1,00 ± 0,17 vs 0,88 ± 0,20) mm, p < 0,001] et la proportion des patients avec plaques carotidiennes (44/88 vs 20/87 p < 0,001) dans le quartile le plus bas de 25(OH)D étaient plus élevés que dans le quartile le plus élevé. Les concentrations en vitamine D étaient inversement associées à l’HbA1c chez les femmes (r = −0,194, p = 0,006),
∗
Corresponding author. E-mail address: [email protected] (X.-z. Jiang).
http://dx.doi.org/10.1016/j.ando.2014.07.113 0003-4266/© 2014 Published by Elsevier Masson SAS.
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et C-IMT chez les hommes (r = −0,409, p < 0,001). L’analyse de régression logistique a montré que l’âge, le sexe masculin, le tabagisme, des antécédents d’hypertension, la pression artérielle systolique, le LDL-C et une lg [25(OH)D] (OR: 0,924, IC à 95 %: 0.893–0 0,955, p < 0,001) étaient associés d’une fac¸on indépendante avec la présence de plaques carotidiennes dans le DT2. Conclusions. – Le taux sérique de vitamine D est significativement et indépendamment associé à une athérosclérose carotidienne chez les patients atteints de DT2 à Shanghai. © 2014 Publié par Elsevier Masson SAS. Mots clés : Diabète de type 2 ; 25-hydroxyvitamine D ; Athérosclérose subclinique ; Épaisseur intima-média carotidienne
1. Introduction The prevalence of type 2 diabetes (T2DM) is rapidly increasing and it has become a major health problem in recent years in Asia [1,2]. Over time, particular damage to organs may ensue, among which macrovascular complications are the main leading cause of morbidity and mortality, and cardiovascular disease (CVD) risk is 2- to 8-fold higher in the diabetic population than it is in non-diabetic individuals of a similar age, sex and ethnicity [3,4]. Vitamin D deficiency has been recognized as a worldwide concern [5] and is highly prevalent in China [6]. There is accumulating evidence suggesting that serum concentrations of 25-hydroxyvitamin D [25(OH)D] may be inversely associated with type 2 diabetes [7], metabolic syndrome [6], and cardiovascular disease (CVD) [8], even though the underlying mechanism has not been well understood. However, the correlations of vitamin D concentrations with atherosclerosis are controversial in different populations [9–12]. Targher et al. [13] reported an inverse association between 25(OH)D and IMT among 390 diabetic patients in Italy. Because of ethnic and regional differences in vitamin D metabolism and its nutritional status between eastern and western area, it is not clear whether the findings from western populations could be extrapolated directly to Asian individuals. Besides, little is known regarding whether vitamin D deficiency is correlated with carotid atherosclerosis among Asian diabetic patients. In the present study, we sought to assess the nutritional status of vitamin D and investigate the association of 25-hydroxyvitamin D concentrations and carotid atherosclerosis in patients with type 2 diabetes in Shanghai, China. 2. Methods 2.1. Subjects Patients with T2DM fulfilling the entry criteria were recruited randomly from the diabetic outpatient department of our hospital using simple random sampling during the winter months (November–February) from 2011 to 2012 in Shanghai (latitude 31◦ north), China. A total of 350 type 2 diabetic patients were enrolled in this study. Subjects with a clinical history of CVD, cerebrovascular disease, neurological abnormalities, cerebral hemorrhage, or malignancy, and those who were taking any medications known to affect vitamin D metabolism, including vitamin/mineral supplements, were excluded. The study was carried out in accordance with the Declaration of Helsinki (2000)
of the World Medical Association. The local Ethics Committee approved the protocol. Written informed consent was obtained from all participants. 2.2. Clinical evaluation All the subjects received an interview including age, gender, history of smoking, history of drinking, history of hypertension. Data of waist circumference, body mass index (BMI), and blood pressure was collected. Hypertension was defined as systolic or diastolic blood pressure ≥ 140 mmHg, or 90 mmHg respectively, or self-reported current use of blood pressure lowering medication. 2.3. Laboratory methods Blood samples were obtained by venipuncture after an overnight fast and placed into tubes that were protected from sunlight. All the tests were preceded in local laboratory. Serum 25(OH)D [25(OH)D2 + 25(OH)D3 ] was measured using electro-chemiluminescence immuno-assay (Cobas 6000 analyzer, Roche, USA). The intra-assay coefficient of variation (CV) was < 13.7% and the interassay CV was < 8%, respectively. The limit of detection was 4.00 ng/ml and the reference range was 4.00–75.00 ng/ml. Vitamin D deficiency was defined as a serum 25(OH)D concentration < 20 ng/ml and insufficiency as serum 25(OH)D concentration < 30 ng/ml. Fasting blood glucose (FBG), Serum creatinine (Scr), triglyceride (TG), total cholesterol (TC), low-density cholesterol (LDL-C), highdensity cholesterol (HDL-C) were measured enzymatically on an automatic analyzer (Cobas 8000 C701 C502 autochemistry analyzer, Roche, USA), HaemoglobinA1c (HbA1c) was quantified from resolved erythrocytes with high performance liquid chromatography (HPLC) (HLC-723G7 analyzer, TOSOH kabushiki kaisha, Japan). Estimated glomerular filtration rate (e-GFR) was calculated with the simplified equation proposed by the Modification of Diet in Renal Disease (MDRD) Study Group. 2.4. Ultrasonography of carotid arteries The measurements of IMT and determination of atheroma in the extracranial carotid wall were performedusing the highresolution B mode ultrasound equipment (Sequoia scanner, Siemens, Germany). Measurements of IMT were obtained on the anterior and posterior walls of the right and left carotid [14] arteries as follows: three measurements on the carotid
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artery one centimeter proximal to the bifurcation, one measurement in the carotid bulb and two measurements in the first inch of the internal carotid artery. We used the maximum mean of the thickness of each segment for the final analysis. Carotid plaque is defined as the presence of focal wall thickening that is at least 50% greater than that of the surrounding vessel wall or as a focal region with CIMT greater than 1.5 mm that protrudes into the lumen that is distinct from the adjacent boundary [15]. 2.5. Statistical analyses All continuous data were tested for normality using Kolmogorov-Smirnov (KS) test. Because of skewness and kurtosis of the distributions, serum TG and 25(OH)D concentrations were logarithmically transformed for regression analyses and then back-transformed to their natural units for presentation in text and tables. The Chi2 test was used for comparison of categorical variables. Statistical analysis was performed for comparison between two groups (variables) with independent t-test for continuous data. One way Anova was performed to analyze the P-value of trends of clinical variables among quartiles of vitamin D concentrations. Pearson’s tests and spearman tests were used to correlate normally and non-normally distributed variables. Multivariate logistic regression analysis was used to perform multivariate analysis and define independent predictors. These analyses were performed using the Statistical Package for the Social Science (SPSS Version 19.0, IBM, USA). Results are expressed as mean (SD). A P-value of less than 0.05 was considered to be significant. 3. Results On average, the 350 type 2 diabetic patients included in this study were aged 58.6 ± 8.9 (range 38–80) years, 56.3% were women. The mean (± SD) BMI was 25.79 ± 3.18 kg/m2 , and the mean waist circumference was 87.15 ± 8.69 cm. The mean concentration of 25(OH)D was 22.89 ± 8.99 ng/ml (median: 21.75 ng/ml, range: 6.21–57.06 ng/ml) among all the patients. The prevalence of 25(OH)D levels < 20 or < 30 ng/ml was 40.0% and 78.9%, respectively. Medication use of study participants in two groups are summarized in Table 1. No statistical differences were found in medication use between two groups. As shown in Table 2, patients with carotid plaques (group A) were older than those without carotid plaques (group B). Proportion of male, habitual alcohol drinker, current smoker, hypertension, 25(OH)D < 20 ng/ml and 25(OH)D < 30 ng/ml were higher in group A than in group B (P < 0.05). Comparing with group B, patients in group A had a significantly longer duration of diabetes, elevated SBP, HbA1c, LDL-C, C-IMT, and lower 25(OH)D concentrations (P < 0.05). When patients were divided into quartiles by 25(OH)D concentration, the geometric mean of HbA1c (Ptrend = 0.002) and C-IMT (Ptrend < 0.001) were lower, and HDL-C
(Ptrend < 0.001) were higher for patients in the highest quartile compared with those in the lowest (Table 3). We analyzed the correlation of HbA1c, C-IMT and HDL-C with lg[25(OH)D] in different genders. The results showed that HbA1c was significantly correlated with lg[25(OH)D] in women (r = −0.194, P = 0.006) (Fig. 1b) but not in men (r = −0.128, P = 0.115) (Fig. 1a). However, C-IMT, was inversely correlated with lg[25(OH)D] in men (r = −0.409, P < 0.001) (Fig. 2a) but not in women (r = −0.065, P = 0.362) (Fig. 2b). Only HDLC was associated with lg[25(OH)D] in both men (r = 0.218, P = 0.007) and women (r = 0.272, P < 0.001). A logistic regression model, that included the presence of carotid plaques as the dependant variable and age, sex, duration of diabetes, history of hypertension, alcohol drink, current smoke, SBP, HbA1c, LDL-C and lg[25(OH)D] as covariates, the results showed that age, male sex, current smoke, history of hypertension, SBP, HbA1c, LDL-C and lg[25(OH)D] were independent indicators of carotid plaque(P < 0.05) (Table 4). 4. Discussion Our study showed relatively higher proportion of vitamin D deficiency and insufficiency in individuals with carotid atherosclerosis than in controls amongst type 2 diabetic patients. Serum 25(OH)D concentrations were lower in patients with carotid plaques than those without. The C-IMT levels and proportion of people with carotid plaques in the lowest quartile of 25(OH)D were higher than in the highest quartile. It was revealed that lg[25(OH)D] was positively correlated with HDLC. In male patients, lg[25(OH)D] was inversely associated with carotid artery IMT, but not associated with HbA1c. In female patients, lg[25(OH)D] was correlated with HbA1c, but not IMT. Notably, 25(OH)D concentrations were inversely associated with carotid atherosclerosis independent of age, sex, blood pressure, glycaemic control and blood lipids. Several studies have demonstrated that vitamin D3 might have following biological actions which may play a protective role against atherosclerosis: 1,25-dihy-droxyvitamin D3 can inhibit renin synthesis [16], increase insulin production [17] and predict better -cell function [18], and increase myocardial contractility [19]. Notably, OH et al. [20] found that 1,25(OH)2 vitamin D might inhibit foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes only, comparing with obese, non-diabetic, and hypertensive patients. Previous studies have showed that increased C-IMT and presence of carotid artery plaques determined with B-mode ultrasound were early signs of atherosclerosis, and they could partially predict the risk of future CVD [21–23]. Recently, many investigators have discussed the relationship between vitamin D and macrovascular atherosclerosis. However, results were contradictory inconsistent. Alele et al. [24] suggested that vitamin D status had no significant impact on the incidence of vascular events in a cohort of high-risk veterans with diabetes in which traditional risk factors were managed according to current treatment guidelines. Also, Sachs et al. [25] found no evidence linking impaired vitamin D metabolism with increased subclinical atherosclerosis in type 1 diabetes. However, Jared
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Table 1 Comparison of medication use between two groups. Group B (n = 223)
Group A (n = 127) Diet only The use of insulin (%) Sulfonylureas (%) Nateglinide or repaglinide Biguanides (%) Thiazolidinediones (%) Glucosidase inhibitor (%) Diuretics (%) - Blockers (%) ACEI (%) ARB (%) CCB (%) Antiplatelet medications (%) Lipid-lowering medications (%)
6 (4.7) 23 (18.1) 44 (34.6) 12 (9.4) 52 (40.9) 16 (12.6) 14 (11.1) 10 (7.9) 2 (1.6) 34 (26.8) 17 (13.4) 30 (23.6) 12 (9.4) 10 (7.9)
22 (9.9) 55 (24.7) 89 (39.9) 16 (7.2) 79 (35.4) 21 (9.4) 36 (16.1) 10 (4.5) 6 (2.7) 44 (19.7) 22 (9.9) 41 (18.4) 16 (720) 20 (9.0)
2
P
2.906 2.007 0.952 0.568 1.052 0.866 1.661 1.726 0.451 2.316 1.013 1.372 0.568 0.124
0.088 0.157 0.329 0.451 0.305 0.352 0.197 0.189 0.502 0.128 0.314 0.241 0.451 0.725
ACEI: Angiotensin-converting enzyme inhibitors; ARB: Angiotensin II receptor blockers; CCB: Calcium channel blockers; 2 test was used to test for significant differences. All values were > 0.05. Table 2 Comparison of demographic and clinical characteristics of type 2 diabetic patients with and without subclinical atherosclerosis. Characteristic Age,mean (SD), years Men, no (%) Duration of DM, mean (SD), years BMI, mean (SD), kg/m2 Waist circumference Habitual alcohol drinker, no (%) Current smoker, no (%) Hypertension (%) SBP, mean (SD), mmHg DBP, mean (SD), mmHg FBG, mean (SD), mmol/L HbA1c, mean (SD), % TC, mean (SD), mmol/L TG, median (25%–75%), mmol/L HDL-C, mean (SD), mmol/L LDL-C, mean (SD), mmol/L eGFR, mean (SD), ml/min per 1.73 m2 25(OH)D < 20 ng/ml 25(OH)D < 30 ng/ml 25(OH)D, median (25%–75%) ng/ml C-IMT, mean (SD), mm
All
Group A (n = 127)
58.61 (8.92) 153 (43.7) 4.77 (4.47) 25.79 (3.18) 87.15 (8.69) 36 (10.3) 67 (19.1) 214 (61.1) 134.51 (16.30) 84.79 (9.04) 8.58 (3.22) 6.92 (1.66) 5.27 (1.01) 1.63 (0.47–17.08) 1.36 (0.37) 3.19 (0.83) 108.71 (29.42) 140 (40.0) 276 (78.9) 23.54 (19.79–30.37) 0.91 (0.19)
62.02 (7.63) 70 (55.1) 5.69 (5.22) 25.68 (3.06) 87.21 (8.55) 24 (18.9) 37 (29.1) 97 (76.4) 138.94 (15.09) 85.71 (9.71) 9.00 (3.24) 7.18 (1.59) 5.39 (1.07) 1.72 (1.12–2.47) 1.36 (0.38) 2.88 (0.79) 109.08 (28.74) 69 (54.3) 109 (85.8) 19.60 (13.30–25.73) 1.05 (0.16)
Group B (n = 223) 56.66 (9.04) 83 (37.2) 4.24 (3.91) 25.85 (3.26) 87.12 (8.79) 12 (5.4) 30 (13.5) 117 (52.5) 131.99 (16.45) 84.27 (8.60) 8.34 (3.20) 6.78 (1.69) 5.20 (0.97) 1.60 (1.04–2.39) 1.33 (0.39) 2.87 (0.78) 108.16 (29.25) 71 (31.8) 167 (74.9) 23.19 (18.10–30.06) 0.83 (0.17)
t/2
P-value
6.894 10.535 2.709 –0.508 0.088 16.020 12.855 19.473 3.914 1.435 1.855 2.175 1.657 0.788 0.049 3.467 –0.155 16.132 12.857 –4.403 11.717
< 0.001 0.001 0.007 0.612 0.930 < 0.001 < 0.001 < 0.001 < 0.001 0.152 0.064 0.030 0.098 0.431 0.961 < 0.001 0.909 < 0.001 < 0.001 < 0.001 < 0.001
BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; FBG: fasting blood glucose; HbA1c: haemoglobinA1c; TC: total cholesterol; TG: triglycerides; HDL-C: high-density cholesterol; LDL-C: low-density cholesterol; C-IMT: common carotid IMT; e-GFR: estimated glomerular filtration rate.
et al. [9] found that internal carotid IMT was inversely associated with 25(OH)D amongst community-dwelling older adults. All evidence above was from USA. On the other hand, study of Targher et al. showed 25(OH)D was inversely associated with IMT in diabetic patients [13], but with no association in another study of 109 postmenopausal women [26] in Italy. In addition, Brøndum-Jacobsen et al. [27] observed increasing risk of ischemic heart disease, myocardial infarction, and early death with decreasing plasma 25-hydroxyvitamin D levels in Denmark. It seemed that different criteria and demography of enrolled subjects in different latitudes and altitudes have different ranges of vitamin D concentrations, and that may contribute
to different correlations between vitamin D and atherosclerosis. In our study, we observed an independent association between serum 25(OH)D levels and presence of carotid plaques, which suggested low 25(OH)D concentration as risk marker of carotid atherosclerosis among type 2 diabetic patients in Shanghai, China. Although the OR for 25(OH)D was mild, and the result showed a weak association between 25(OH)D and carotid atherosclerosis. We speculate it might be because other factors such as hypertension, blood glucose, smoking, blood lipids might play more important roles in the initiation and development of CVD. Also, the small sample size might result in a relatively weak association. A recent study on association
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Table 3 Clinical characteristics of diabetic patients by quartiles of serum 25(OH)D levels. Q1 (6.21–16.65) ng/ml (n = 88) Mean 25(OH)D (ng/ml) Age, mean (SD), years Men, no (%) Duration of DM, mean (SD), years BMI, mean (SD), kg/m2 Waist circumference mean (SD), cm Habitual alcohol drinker, no (%) Current smoker, no (%) Hypertension (%) SBP, mean (SD), mmHg DBP, mean (SD), mmHg FBG, mean (SD), mmol/L HbA1c, mean (SD), % TC, mean (SD), mmol/L TG, median (SD), mmol/L HDL-C, mean (SD), mmol/L LDL-C, mean (SD), mmol/L eGFR, mean (SD), ml/min per 1.73 m2 C-IMT, mean (SD), mm Carotid plaque, no (%)
12.41 (2.83) 57.58 (7.47) 47 (53.4) 5.36 (4.63) 25.50 (2.64) 86.31 (7.82) 9 (10.2) 19 (21.6) 49 (55.7) 133.58 (15.37) 86.68 (7.71) 9.20 (3.01) 7.45 (1.52) 5.08 (0.96) 2.53 (1.99) 1.17 (0.33) 2.92 (0.86) 107.72 (30.40) 1.00 (0.17) 44 (50.0)
Q2 (16.74–21.70) ng/ml (n = 87) 19.38 (1.41) 59.18 (8.97) 30 (34.5) 4.59 (4.38) 26.25 (3.45) 87.99 (9.31) 8 (9.2) 16 (18.4) 60 (69.0) 132.53 (16.91) 83.21 (9.67) 8.5 (2.74) 7.05 (1.53) 5.36 (1.18) 1.78 (1.00) 1.39 (0.37) 3.15 (0.86) 110.79 (29.81) 0.87 (0.19) 36 (41.4)
Q3 (21.80–28.37) ng/ml (n = 88) 24.87 (1.97) 59.50 (9.81) 26 (29.5) 4.48 (4.27) 25.84 (3.18) 86.64 (8.86) 8 (9.1) 14 (15.9) 57 (64.7) 136.65 (14.46) 83.64 (9.18) 7.81 (2.56) 6.29 (1.75) 5.27 (0.87) 2.14 (2.04) 1.50 (0.32) 2.95 (0.74) 109.89 (26.79) 0.90 (0.18) 27 (30.7)
Q4 (28.40–57.06) ng/ml (n = 87) 34.99 (6.05) 58.16 (9.29) 50 (57.5) 4.63 (4.36) 25.68 (3.40) 87.70 (8.76) 11 (12.6) 18 (20.7) 48 (55.2) 135.26 (18.20) 85.63 (9.18) 8.76 (4.23) 6.89 (1.66) 5.36 (0.99) 2.11 (1.61) 1.38 (0.41) 2.96 (0.79) 107.37 (29.05) 0.88 (0.20) 20 (23.0)
Fig. 1. a: Correlations of HbA1c with lg[25(OH)D] in men; b: Correlations of HbA1c with lg[25(OH)D] in women.
Fig. 2. a: Correlations of C-IMT with lg[25(OH)D] in men; b: Correlations of C-IMT with lg[25(OH)D] in women.
P-value for trend – 0.630 0.777 0.285 0.775 0.498 0.626 0.779 0.815 0.240 0.280 0.176 0.002 0.122 0.105 < 0.001 0.833 0.888 < 0.001 < 0.001
R.-h. Chen et al. / Annales d’Endocrinologie 75 (2014) 206–212 Table 4 Multivariate logistic regression analysis of the determinants of carotid plaque (R2 = 0.382).
Age Sex (male) LDL-C Current smoke Hypertension SBP HbA1c lg[25(OH)D]
OR(95%CI)
P-value
1.086 (1.049–1.124) 2.232 (1.249–3.988) 1.625 (1.162–2.274) 4.967 (1.872–13.183) 2.391 (1.311–4.363) 1.018 (1.001–1.037) 1.225 (1.036–1.339) 0.924 (0.893–0.955)
< 0.001 0.007 0.005 0.001 0.004 0.043 0.018 < 0.001
of serum 25-hydroxyvitamin D3 Levels with atherosclerosis in 1001 middle-aged and elderly men also showed a relatively mild OR[(95% CI): 0.972 (0.946–0.998), P = 0.032)] for 25(OH)D with carotid plaques [28]. Even though, since hypovitaminosis D is highly prevalent and low vitamin D level predicts higher risk of carotid atherosclerosis in our study as well as in some other studies we mentioned above, more attention should be paid to the biochemical mechanism and clinical effect of vitamin D on the prevention of macrovascular disease in patients with type 2 diabetes. In this study, we found 25(OH)D was inversely associated with C-IMT in men, but inversely correlated with HbA1c in women among patients with type 2 diabetes. Hao Y et al. [28] found that decreasing serum 25(OH)D3 levels were accompanied by increased C-IMT in Chinese middle-aged and elderly men. However, no study was performed on the association between 25(OH)D and IMT in diabetic women. Hartaigh et al. [29] found higher serum 25(OH)D levels were associated with better glycaemic status among patients undergoing coronary angiography. But they did not mention the difference between male and female. Study of Manickam et al. [30] showed that the 25(OH)D level is an independent determinant of HbA1c in African American men, but not in Caucasian American men, including men with and without diabetes, suggesting that the threshold of the vitamin D effect on HbA1c may be different between different races. Klop B et al. [31] found vitamin D3 probably increased postprandial arterial elasticity in both genders, but reduced postprandial leukocyte activation only in women. These findings indicate that hypovitaminosis D may affect male and female patients in different ways (multi-ways). Physiological mechanisms accounting for differences between men and women include the possibility that obesity varies by gender [30]. On the other hand, vitamin D insufficiency may contribute to hyperglycemia and obesity, both of which are risk factors of atherosclerosis, by affecting muscle strength and physical activity [32], and the process of energy metabolism might be different in men and women. More studies are needed to explore the potential different biological mechanisms in patients of different genders. Our study is limited by its cross-sectional design, and residual confounding and reverse causation are potential concerns, as in any cross-sectional study. Also, a one-time 25(OH)D measurement may not reflect lifetime vitamin D status. Besides, all the findings correspond to carotid atherosclerosis are not
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necessarily coronary atherosclerosis as well as cardiovascular events. Cohort studies are very necessary to figure out the association of vitamin D deficiency and future cardiovascular events in patients with type 2 diabetes in Shanghai. In addition, our results may not be generalizable to others living in different geographical latitudes and altitudes with differing sunlight exposure in China. The sample size in our study was relatively small, so it remains a possibility that a real association between 25(OH)D and carotid IMT among female patients, and glucose control among male patients exists and that our study was underpowered to detect it. In conclusion, our study indicates that a lower level of serum 25(OH)D in patients with type 2 diabetes is associated with carotid atherosclerosis. 25(OH)D may be associated with C-IMT, particularly in men, and glucose control in women. A reduction of serum 25(OH)D may independently predict subclinical atherosclerosis in diabetic patients. Results of our findings suggest the need for evaluation of the possible protective role of vitamin D in glucose control and the development of atherosclerosis in patients with type 2 diabetes in Shanghai. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements This work was supported by a joint research project of Shanghai health bureau (2010Y047, to R.C) and Shanghai Pudong New Area health bureau (PW2010B-6, PWRq2012-09, to R.C). X.J reviewed and edited the manuscript. R.C designed the study, wrote the manuscript, and researched data. Q.J performed all the carotid artery ultrasound. Z.G, P.G, B.Z, Z.Z, L.X, Y.Q, Y.Z researched data. References [1] Yang W, Lu J, Weng J, Jia W, Ji L, Xiao J, et al. Prevalence of diabetes among men and women in China. N Engl J Med 2010;362:1090–101. [2] Lin C-C, Li C-I, Hsiao C-Y, Liu C-S, Yang S-Y, Lee C-C, et al. Time trend analysis of the prevalence and incidence of diagnosed type 2 diabetes among adults in Taiwan from 2000 to 2007: a population-based study. BMC Public Health 2013;13:318. [3] Brun E, Nelson RG, Bennett PH, Imperatore G, Zoppini G, Verlato G, et al. Diabetes duration and cause-specific mortality in the Verona Diabetes Study. Diabetes Care 2000;23:1119–23. [4] Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229–34. [5] Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81. [6] Lu L, Yu Z, Pan A, Hu FB, Franco OH, Li H, et al. Plasma 25hydroxyvitamin D concentration and metabolic syndrome among middleaged and elderly Chinese individuals. Diabetes Care 2009;32:1278–83. [7] Lim S, Kim MJ, Choi SH, Shin CS, Park KS, Jang HC, et al. Association of vitamin D deficiency with incidence of type 2 diabetes in high-risk Asian subjects. Am J Clin Nutr 2013;97:524–30. [8] Wang L, Song Y, Manson JE, Pilz S, März W, Michaëlsson K, et al. Circulating 25-hydroxyvitamin D and risk of cardiovascular disease: a
212
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16] [17]
[18]
[19] [20]
R.-h. Chen et al. / Annales d’Endocrinologie 75 (2014) 206–212 meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes 2012;5:819–29. Reis JP, von Mühlen D, Michos ED, Miller ER, Appel LJ, Araneta MR, et al. Serum vitamin D, parathyroid hormone levels, and carotid atherosclerosis. Atherosclerosis 2009;207:585–90. Cheraghi N, Dai H, Raghuveer G. Vitamin D deficiency is associated with atherosclerosis-promoting risk factor clustering but not vascular damage in children. Med Sci Monit 2012;18:CR687–92. Michos ED, Streeten EA, Ryan KA, Rampersaud E, Peyser PA, Bielak LF, et al. Serum 25-hydroxyvitamin D levels are not associated with subclinical vascular disease or C-reactive protein in the old order Amish. Calcif Tissue Int 2009;84:195–202. Knox S, Welsh P, Bezlyak V, McConnachie A, Boulton E, Deans KA, et al. 25-hydroxyvitamin D is lower in deprived groups, but is not associated with carotid intima media thickness or plaques: results from pSoBid. Atherosclerosis 2012;223:437–41. Targher G, Bertolini L, Padovani R, Zenari L, Scala L, Cigolini M, et al. Serum 25-hydroxyvitamin D3 concentrations and carotid artery intimamedia thickness among type 2 diabetic patients. Clin Endocrinol (Oxf) 2006;65:593–7. Stein JH, Korcarz CE, Post WS. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: summary and discussion of the American Society of echocardiography consensus statement. Prev Cardiol 2009;12:34–8. Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of echocardiography carotid intima-media thickness task force endorsed by the Society for vascular medicine. J Am Soc Echocardiogr 2008;21:93–111. Li YC. Vitamin D regulation of the renin-angiotensin system. J Cell Biochem 2003;88:327–31. Chiu KC, Chu A, Go VLW, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta-cell dysfunction. Am J Clin Nutr 2004;79:820–5. Kayaniyil S, Retnakaran R, Harris SB, Vieth R, Knight JA, Gerstein HC, et al. Prospective associations of vitamin D with -cell function and glycemia: the PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study. Diabetes 2011;60:2947–53. Zittermann A. Vitamin D and disease prevention with special reference to cardiovascular disease. Prog Biophys Mol Biol 2006;92:39–48. Weng S, Felton SK, Bhandare S, Riek A, Butler B, Proctor BM, et al. 1,25(OH)2 vitamin D inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus. Circulation 2009;120:687–98.
[21] Jeevarethinam A, Venuraju S, Weymouth M, Atwal S, Lahiri A. Carotid intimal thickness and plaque predict prevalence and severity of coronary atherosclerosis: a pilot study. Angiology 2014. [22] Pursnani S, Diener-West M, Sharrett AR. The effect of aging on the association between coronary heart disease risk factors and carotid intima media thickness: an analysis of the atherosclerosis risk in communities (ARIC) cohort. Atherosclerosis 2014;233:441–6. [23] Kawamoto R, Katoh T, Kusunoki T, Ohtsuka N. Carotid atherosclerosis as a surrogate maker of cardiovascular disease in diabetic patients. ISRN Endocrinol 2013;2013:979481. [24] Alele JD, Luttrell LM, Hollis BW, Luttrell DK, Hunt KJ, VADT Study Group. Relationship between vitamin D status and incidence of vascular events in the veterans affairs diabetes trial. Atherosclerosis 2013;228:502–7. [25] Sachs MC, Brunzell JD, Cleary PA, Hoofnagle AN, Lachin JM, Molitch ME, et al. Circulating vitamin D metabolites and subclinical atherosclerosis in type 1 diabetes. Diabetes Care 2013. [26] Choi HS, Kim SH, Rhee Y, Cho MA, Lee EJ, Lim S-K. Serum parathyroid hormone is associated with carotid intima-media thickness in postmenopausal women. Int J Clin Pract 2008;62:1352–7. [27] Brøndum-Jacobsen P, Benn M, Jensen GB, Nordestgaard BG. 25hydroxyvitamin d levels and risk of ischemic heart disease, myocardial infarction, and early death: population-based study and meta-analyses of 18 and 17 studies. Arterioscler Thromb Vasc Biol 2012;32:2794– 802. [28] Hao Y, Ma X, Luo Y, Ni J, Dou J, Zhu J, et al. Additional role of serum 25-hydroxyvitamin D3 levels in atherosclerosis in Chinese middle-aged and elderly men. Clin Exp Pharmacol Physiol 2014. [29] O’Hartaigh B, Neil Thomas G, Silbernagel G, Bosch JA, Pilz S, Loerbroks A, et al. Association of 25-hydroxyvitamin D with type 2 diabetes among patients undergoing coronary angiography: cross-sectional findings from the LUdwigshafen Risk and Cardiovascular Health (LURIC) Study. Clin Endocrinol (Oxf) 2013;79:192–8. [30] Manickam B, Neagu V, Kukreja SC, Barengolts E. Relationship between glycated hemoglobin and circulating 25-hydroxyvitamin D concentration in African American and Caucasian American men. Endocr Pract 2013;19:73–80. [31] Klop B, van de Geijn G-J, Birnie E, Njo TL, Janssen HW, Jansen HG, et al. Vitamin D3 mediated effects on postprandial leukocyte activation and arterial stiffness in men and women. Eur J Clin Nutr 2014. [32] Muir SW, Montero-Odasso M. Effect of vitamin D supplementation on muscle strength, gait and balance in older adults: a systematic review and meta-analysis. J Am Geriatr Soc 2011;59:2291–300.
ScienceDirect www.sciencedirect.com Annales d’Endocrinologie 75 (2014) 206–212
Original article
Correlations between serum levels of 25-hydroxyvitamin D and carotid atherosclerosis in patients with type 2 diabetes in Shanghai Corrélations entre taux sériques de 25-hydroxyvitamine D et athérosclérose carotidienne chez les patients atteints de diabète de type 2 à Shanghai Rui-hua Chen a , Xiao-zhen Jiang a,∗ , Quan Jiang b , Zhe Gu a , Pei-li Gu a , Bin Zhou a , Zhen-hong Zhu a , Lin-yan Xu a , Yu-feng Zou a a
Department of endocrinology, Pudong New Area People’s Hospital, 490, South Chuan Huan Road, Shanghai, China b Department of ultrasonography, Shanghai Pudong New Area People’s Hospital, Shanghai, China
Abstract Objective. – To explore the potential association between the serum levels of 25-hydroxyvitamin D [25(OH)D] and carotid atherosclerosis in patients with type 2 diabetes. Material and methods. – Three hundred and fifty patients with type 2 diabetes were enrolled in this study in Shanghai, China. B-mode ultrasound was used to detect carotid plaques as indicators of atherosclerosis and measure carotid artery intima-media wall thickness (C-IMT) at two sites of carotid artery. Subjects were divided into group A (patients with carotid plaques) and group B (patients without carotid plaques) and be assessed clinically. Serum levels of 25(OH)D and other clinical parameters were measured. Multivariate logistic regression was performed to find predictors of carotid atherosclerosis in the entire group. Results. – The levels of serum 25(OH)D were lower in group A than in group B[19.60 (13.30–25.73) vs 23.19 (18.10–30.06) ng/ml, P < 0.001]. The C-IMT levels [(1.00 ± 0.17 vs 0.88 ± 0.20) mm, Ptrend < 0.001] and proportion of people with carotid plaques(44/88 vs 20/87, Ptrend < 0.001) in the lowest quartile of 25(OH)D were higher than in the highest quartile. Vitamin D concentrations were inversely associated with HbA1c in women(r = −0.194, P = 0.006), and C-IMT in men(r = −0.409, P < 0.001). Logistic regression analysis showed age, male sex, current smoke, history of hypertension, SBP, LDL-C and lg[25(OH)D] (OR: 0.924, 95%CI: 0.893–0.955, P < 0.001) were independently associated with the presence of carotid plaques in T2DM. Conclusions. – Serum vitamin D level is significantly and independently associated with carotid atherosclerosis in patients with T2DM in Shanghai, China. © 2014 Published by Elsevier Masson SAS. Keywords: Diabetes mellitus type 2; 25-hydroxyvitamin D; Atherosclerosis; Carotid intima-media thickness
Résumé Objectif. – Explorer l’association potentielle entre les taux sériques de 25-hydroxyvitamine D [25(OH)D] et l’athérosclérose carotidienne chez les patients atteints de diabète de type 2. Matériel et méthodes. – Trois cent cinquante patients atteints de diabète de type 2 ont été inclus dans cette étude menée à Shanghai, en Chine. L’échographie en mode B a été utilisée pour détecter les plaques carotidiennes indiquant une athérosclérose et mesurer l’épaisseur de la paroi intima-média carotidienne (C-IMT) en deux endroits de l’artère carotide. Les patients ont été divisés en groupe A (patients atteints de plaques carotidiennes) et groupe B (patients sans plaques carotidiennes) et évalués cliniquement. Les niveaux sérologiques de 25 (OH) D et d’autres paramètres cliniques ont été mesurés. Une régression logistique multivariée a été effectuée pour trouver des prédicateurs de l’athérosclérose carotidienne dans l’ensemble du groupe. Résultats. – Les taux sériques de 25(OH)D étaient plus faibles dans le groupe A que dans le groupe B [19,60 (13,30 à 25,73) vs 23,19 (18,10 à 30,06) ng/mL, p < 0,001]. Les niveaux C-IMT [(1,00 ± 0,17 vs 0,88 ± 0,20) mm, p < 0,001] et la proportion des patients avec plaques carotidiennes (44/88 vs 20/87 p < 0,001) dans le quartile le plus bas de 25(OH)D étaient plus élevés que dans le quartile le plus élevé. Les concentrations en vitamine D étaient inversement associées à l’HbA1c chez les femmes (r = −0,194, p = 0,006),
∗
Corresponding author. E-mail address: [email protected] (X.-z. Jiang).
http://dx.doi.org/10.1016/j.ando.2014.07.113 0003-4266/© 2014 Published by Elsevier Masson SAS.
R.-h. Chen et al. / Annales d’Endocrinologie 75 (2014) 206–212
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et C-IMT chez les hommes (r = −0,409, p < 0,001). L’analyse de régression logistique a montré que l’âge, le sexe masculin, le tabagisme, des antécédents d’hypertension, la pression artérielle systolique, le LDL-C et une lg [25(OH)D] (OR: 0,924, IC à 95 %: 0.893–0 0,955, p < 0,001) étaient associés d’une fac¸on indépendante avec la présence de plaques carotidiennes dans le DT2. Conclusions. – Le taux sérique de vitamine D est significativement et indépendamment associé à une athérosclérose carotidienne chez les patients atteints de DT2 à Shanghai. © 2014 Publié par Elsevier Masson SAS. Mots clés : Diabète de type 2 ; 25-hydroxyvitamine D ; Athérosclérose subclinique ; Épaisseur intima-média carotidienne
1. Introduction The prevalence of type 2 diabetes (T2DM) is rapidly increasing and it has become a major health problem in recent years in Asia [1,2]. Over time, particular damage to organs may ensue, among which macrovascular complications are the main leading cause of morbidity and mortality, and cardiovascular disease (CVD) risk is 2- to 8-fold higher in the diabetic population than it is in non-diabetic individuals of a similar age, sex and ethnicity [3,4]. Vitamin D deficiency has been recognized as a worldwide concern [5] and is highly prevalent in China [6]. There is accumulating evidence suggesting that serum concentrations of 25-hydroxyvitamin D [25(OH)D] may be inversely associated with type 2 diabetes [7], metabolic syndrome [6], and cardiovascular disease (CVD) [8], even though the underlying mechanism has not been well understood. However, the correlations of vitamin D concentrations with atherosclerosis are controversial in different populations [9–12]. Targher et al. [13] reported an inverse association between 25(OH)D and IMT among 390 diabetic patients in Italy. Because of ethnic and regional differences in vitamin D metabolism and its nutritional status between eastern and western area, it is not clear whether the findings from western populations could be extrapolated directly to Asian individuals. Besides, little is known regarding whether vitamin D deficiency is correlated with carotid atherosclerosis among Asian diabetic patients. In the present study, we sought to assess the nutritional status of vitamin D and investigate the association of 25-hydroxyvitamin D concentrations and carotid atherosclerosis in patients with type 2 diabetes in Shanghai, China. 2. Methods 2.1. Subjects Patients with T2DM fulfilling the entry criteria were recruited randomly from the diabetic outpatient department of our hospital using simple random sampling during the winter months (November–February) from 2011 to 2012 in Shanghai (latitude 31◦ north), China. A total of 350 type 2 diabetic patients were enrolled in this study. Subjects with a clinical history of CVD, cerebrovascular disease, neurological abnormalities, cerebral hemorrhage, or malignancy, and those who were taking any medications known to affect vitamin D metabolism, including vitamin/mineral supplements, were excluded. The study was carried out in accordance with the Declaration of Helsinki (2000)
of the World Medical Association. The local Ethics Committee approved the protocol. Written informed consent was obtained from all participants. 2.2. Clinical evaluation All the subjects received an interview including age, gender, history of smoking, history of drinking, history of hypertension. Data of waist circumference, body mass index (BMI), and blood pressure was collected. Hypertension was defined as systolic or diastolic blood pressure ≥ 140 mmHg, or 90 mmHg respectively, or self-reported current use of blood pressure lowering medication. 2.3. Laboratory methods Blood samples were obtained by venipuncture after an overnight fast and placed into tubes that were protected from sunlight. All the tests were preceded in local laboratory. Serum 25(OH)D [25(OH)D2 + 25(OH)D3 ] was measured using electro-chemiluminescence immuno-assay (Cobas 6000 analyzer, Roche, USA). The intra-assay coefficient of variation (CV) was < 13.7% and the interassay CV was < 8%, respectively. The limit of detection was 4.00 ng/ml and the reference range was 4.00–75.00 ng/ml. Vitamin D deficiency was defined as a serum 25(OH)D concentration < 20 ng/ml and insufficiency as serum 25(OH)D concentration < 30 ng/ml. Fasting blood glucose (FBG), Serum creatinine (Scr), triglyceride (TG), total cholesterol (TC), low-density cholesterol (LDL-C), highdensity cholesterol (HDL-C) were measured enzymatically on an automatic analyzer (Cobas 8000 C701 C502 autochemistry analyzer, Roche, USA), HaemoglobinA1c (HbA1c) was quantified from resolved erythrocytes with high performance liquid chromatography (HPLC) (HLC-723G7 analyzer, TOSOH kabushiki kaisha, Japan). Estimated glomerular filtration rate (e-GFR) was calculated with the simplified equation proposed by the Modification of Diet in Renal Disease (MDRD) Study Group. 2.4. Ultrasonography of carotid arteries The measurements of IMT and determination of atheroma in the extracranial carotid wall were performedusing the highresolution B mode ultrasound equipment (Sequoia scanner, Siemens, Germany). Measurements of IMT were obtained on the anterior and posterior walls of the right and left carotid [14] arteries as follows: three measurements on the carotid
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artery one centimeter proximal to the bifurcation, one measurement in the carotid bulb and two measurements in the first inch of the internal carotid artery. We used the maximum mean of the thickness of each segment for the final analysis. Carotid plaque is defined as the presence of focal wall thickening that is at least 50% greater than that of the surrounding vessel wall or as a focal region with CIMT greater than 1.5 mm that protrudes into the lumen that is distinct from the adjacent boundary [15]. 2.5. Statistical analyses All continuous data were tested for normality using Kolmogorov-Smirnov (KS) test. Because of skewness and kurtosis of the distributions, serum TG and 25(OH)D concentrations were logarithmically transformed for regression analyses and then back-transformed to their natural units for presentation in text and tables. The Chi2 test was used for comparison of categorical variables. Statistical analysis was performed for comparison between two groups (variables) with independent t-test for continuous data. One way Anova was performed to analyze the P-value of trends of clinical variables among quartiles of vitamin D concentrations. Pearson’s tests and spearman tests were used to correlate normally and non-normally distributed variables. Multivariate logistic regression analysis was used to perform multivariate analysis and define independent predictors. These analyses were performed using the Statistical Package for the Social Science (SPSS Version 19.0, IBM, USA). Results are expressed as mean (SD). A P-value of less than 0.05 was considered to be significant. 3. Results On average, the 350 type 2 diabetic patients included in this study were aged 58.6 ± 8.9 (range 38–80) years, 56.3% were women. The mean (± SD) BMI was 25.79 ± 3.18 kg/m2 , and the mean waist circumference was 87.15 ± 8.69 cm. The mean concentration of 25(OH)D was 22.89 ± 8.99 ng/ml (median: 21.75 ng/ml, range: 6.21–57.06 ng/ml) among all the patients. The prevalence of 25(OH)D levels < 20 or < 30 ng/ml was 40.0% and 78.9%, respectively. Medication use of study participants in two groups are summarized in Table 1. No statistical differences were found in medication use between two groups. As shown in Table 2, patients with carotid plaques (group A) were older than those without carotid plaques (group B). Proportion of male, habitual alcohol drinker, current smoker, hypertension, 25(OH)D < 20 ng/ml and 25(OH)D < 30 ng/ml were higher in group A than in group B (P < 0.05). Comparing with group B, patients in group A had a significantly longer duration of diabetes, elevated SBP, HbA1c, LDL-C, C-IMT, and lower 25(OH)D concentrations (P < 0.05). When patients were divided into quartiles by 25(OH)D concentration, the geometric mean of HbA1c (Ptrend = 0.002) and C-IMT (Ptrend < 0.001) were lower, and HDL-C
(Ptrend < 0.001) were higher for patients in the highest quartile compared with those in the lowest (Table 3). We analyzed the correlation of HbA1c, C-IMT and HDL-C with lg[25(OH)D] in different genders. The results showed that HbA1c was significantly correlated with lg[25(OH)D] in women (r = −0.194, P = 0.006) (Fig. 1b) but not in men (r = −0.128, P = 0.115) (Fig. 1a). However, C-IMT, was inversely correlated with lg[25(OH)D] in men (r = −0.409, P < 0.001) (Fig. 2a) but not in women (r = −0.065, P = 0.362) (Fig. 2b). Only HDLC was associated with lg[25(OH)D] in both men (r = 0.218, P = 0.007) and women (r = 0.272, P < 0.001). A logistic regression model, that included the presence of carotid plaques as the dependant variable and age, sex, duration of diabetes, history of hypertension, alcohol drink, current smoke, SBP, HbA1c, LDL-C and lg[25(OH)D] as covariates, the results showed that age, male sex, current smoke, history of hypertension, SBP, HbA1c, LDL-C and lg[25(OH)D] were independent indicators of carotid plaque(P < 0.05) (Table 4). 4. Discussion Our study showed relatively higher proportion of vitamin D deficiency and insufficiency in individuals with carotid atherosclerosis than in controls amongst type 2 diabetic patients. Serum 25(OH)D concentrations were lower in patients with carotid plaques than those without. The C-IMT levels and proportion of people with carotid plaques in the lowest quartile of 25(OH)D were higher than in the highest quartile. It was revealed that lg[25(OH)D] was positively correlated with HDLC. In male patients, lg[25(OH)D] was inversely associated with carotid artery IMT, but not associated with HbA1c. In female patients, lg[25(OH)D] was correlated with HbA1c, but not IMT. Notably, 25(OH)D concentrations were inversely associated with carotid atherosclerosis independent of age, sex, blood pressure, glycaemic control and blood lipids. Several studies have demonstrated that vitamin D3 might have following biological actions which may play a protective role against atherosclerosis: 1,25-dihy-droxyvitamin D3 can inhibit renin synthesis [16], increase insulin production [17] and predict better -cell function [18], and increase myocardial contractility [19]. Notably, OH et al. [20] found that 1,25(OH)2 vitamin D might inhibit foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes only, comparing with obese, non-diabetic, and hypertensive patients. Previous studies have showed that increased C-IMT and presence of carotid artery plaques determined with B-mode ultrasound were early signs of atherosclerosis, and they could partially predict the risk of future CVD [21–23]. Recently, many investigators have discussed the relationship between vitamin D and macrovascular atherosclerosis. However, results were contradictory inconsistent. Alele et al. [24] suggested that vitamin D status had no significant impact on the incidence of vascular events in a cohort of high-risk veterans with diabetes in which traditional risk factors were managed according to current treatment guidelines. Also, Sachs et al. [25] found no evidence linking impaired vitamin D metabolism with increased subclinical atherosclerosis in type 1 diabetes. However, Jared
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Table 1 Comparison of medication use between two groups. Group B (n = 223)
Group A (n = 127) Diet only The use of insulin (%) Sulfonylureas (%) Nateglinide or repaglinide Biguanides (%) Thiazolidinediones (%) Glucosidase inhibitor (%) Diuretics (%) - Blockers (%) ACEI (%) ARB (%) CCB (%) Antiplatelet medications (%) Lipid-lowering medications (%)
6 (4.7) 23 (18.1) 44 (34.6) 12 (9.4) 52 (40.9) 16 (12.6) 14 (11.1) 10 (7.9) 2 (1.6) 34 (26.8) 17 (13.4) 30 (23.6) 12 (9.4) 10 (7.9)
22 (9.9) 55 (24.7) 89 (39.9) 16 (7.2) 79 (35.4) 21 (9.4) 36 (16.1) 10 (4.5) 6 (2.7) 44 (19.7) 22 (9.9) 41 (18.4) 16 (720) 20 (9.0)
2
P
2.906 2.007 0.952 0.568 1.052 0.866 1.661 1.726 0.451 2.316 1.013 1.372 0.568 0.124
0.088 0.157 0.329 0.451 0.305 0.352 0.197 0.189 0.502 0.128 0.314 0.241 0.451 0.725
ACEI: Angiotensin-converting enzyme inhibitors; ARB: Angiotensin II receptor blockers; CCB: Calcium channel blockers; 2 test was used to test for significant differences. All values were > 0.05. Table 2 Comparison of demographic and clinical characteristics of type 2 diabetic patients with and without subclinical atherosclerosis. Characteristic Age,mean (SD), years Men, no (%) Duration of DM, mean (SD), years BMI, mean (SD), kg/m2 Waist circumference Habitual alcohol drinker, no (%) Current smoker, no (%) Hypertension (%) SBP, mean (SD), mmHg DBP, mean (SD), mmHg FBG, mean (SD), mmol/L HbA1c, mean (SD), % TC, mean (SD), mmol/L TG, median (25%–75%), mmol/L HDL-C, mean (SD), mmol/L LDL-C, mean (SD), mmol/L eGFR, mean (SD), ml/min per 1.73 m2 25(OH)D < 20 ng/ml 25(OH)D < 30 ng/ml 25(OH)D, median (25%–75%) ng/ml C-IMT, mean (SD), mm
All
Group A (n = 127)
58.61 (8.92) 153 (43.7) 4.77 (4.47) 25.79 (3.18) 87.15 (8.69) 36 (10.3) 67 (19.1) 214 (61.1) 134.51 (16.30) 84.79 (9.04) 8.58 (3.22) 6.92 (1.66) 5.27 (1.01) 1.63 (0.47–17.08) 1.36 (0.37) 3.19 (0.83) 108.71 (29.42) 140 (40.0) 276 (78.9) 23.54 (19.79–30.37) 0.91 (0.19)
62.02 (7.63) 70 (55.1) 5.69 (5.22) 25.68 (3.06) 87.21 (8.55) 24 (18.9) 37 (29.1) 97 (76.4) 138.94 (15.09) 85.71 (9.71) 9.00 (3.24) 7.18 (1.59) 5.39 (1.07) 1.72 (1.12–2.47) 1.36 (0.38) 2.88 (0.79) 109.08 (28.74) 69 (54.3) 109 (85.8) 19.60 (13.30–25.73) 1.05 (0.16)
Group B (n = 223) 56.66 (9.04) 83 (37.2) 4.24 (3.91) 25.85 (3.26) 87.12 (8.79) 12 (5.4) 30 (13.5) 117 (52.5) 131.99 (16.45) 84.27 (8.60) 8.34 (3.20) 6.78 (1.69) 5.20 (0.97) 1.60 (1.04–2.39) 1.33 (0.39) 2.87 (0.78) 108.16 (29.25) 71 (31.8) 167 (74.9) 23.19 (18.10–30.06) 0.83 (0.17)
t/2
P-value
6.894 10.535 2.709 –0.508 0.088 16.020 12.855 19.473 3.914 1.435 1.855 2.175 1.657 0.788 0.049 3.467 –0.155 16.132 12.857 –4.403 11.717
< 0.001 0.001 0.007 0.612 0.930 < 0.001 < 0.001 < 0.001 < 0.001 0.152 0.064 0.030 0.098 0.431 0.961 < 0.001 0.909 < 0.001 < 0.001 < 0.001 < 0.001
BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; FBG: fasting blood glucose; HbA1c: haemoglobinA1c; TC: total cholesterol; TG: triglycerides; HDL-C: high-density cholesterol; LDL-C: low-density cholesterol; C-IMT: common carotid IMT; e-GFR: estimated glomerular filtration rate.
et al. [9] found that internal carotid IMT was inversely associated with 25(OH)D amongst community-dwelling older adults. All evidence above was from USA. On the other hand, study of Targher et al. showed 25(OH)D was inversely associated with IMT in diabetic patients [13], but with no association in another study of 109 postmenopausal women [26] in Italy. In addition, Brøndum-Jacobsen et al. [27] observed increasing risk of ischemic heart disease, myocardial infarction, and early death with decreasing plasma 25-hydroxyvitamin D levels in Denmark. It seemed that different criteria and demography of enrolled subjects in different latitudes and altitudes have different ranges of vitamin D concentrations, and that may contribute
to different correlations between vitamin D and atherosclerosis. In our study, we observed an independent association between serum 25(OH)D levels and presence of carotid plaques, which suggested low 25(OH)D concentration as risk marker of carotid atherosclerosis among type 2 diabetic patients in Shanghai, China. Although the OR for 25(OH)D was mild, and the result showed a weak association between 25(OH)D and carotid atherosclerosis. We speculate it might be because other factors such as hypertension, blood glucose, smoking, blood lipids might play more important roles in the initiation and development of CVD. Also, the small sample size might result in a relatively weak association. A recent study on association
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Table 3 Clinical characteristics of diabetic patients by quartiles of serum 25(OH)D levels. Q1 (6.21–16.65) ng/ml (n = 88) Mean 25(OH)D (ng/ml) Age, mean (SD), years Men, no (%) Duration of DM, mean (SD), years BMI, mean (SD), kg/m2 Waist circumference mean (SD), cm Habitual alcohol drinker, no (%) Current smoker, no (%) Hypertension (%) SBP, mean (SD), mmHg DBP, mean (SD), mmHg FBG, mean (SD), mmol/L HbA1c, mean (SD), % TC, mean (SD), mmol/L TG, median (SD), mmol/L HDL-C, mean (SD), mmol/L LDL-C, mean (SD), mmol/L eGFR, mean (SD), ml/min per 1.73 m2 C-IMT, mean (SD), mm Carotid plaque, no (%)
12.41 (2.83) 57.58 (7.47) 47 (53.4) 5.36 (4.63) 25.50 (2.64) 86.31 (7.82) 9 (10.2) 19 (21.6) 49 (55.7) 133.58 (15.37) 86.68 (7.71) 9.20 (3.01) 7.45 (1.52) 5.08 (0.96) 2.53 (1.99) 1.17 (0.33) 2.92 (0.86) 107.72 (30.40) 1.00 (0.17) 44 (50.0)
Q2 (16.74–21.70) ng/ml (n = 87) 19.38 (1.41) 59.18 (8.97) 30 (34.5) 4.59 (4.38) 26.25 (3.45) 87.99 (9.31) 8 (9.2) 16 (18.4) 60 (69.0) 132.53 (16.91) 83.21 (9.67) 8.5 (2.74) 7.05 (1.53) 5.36 (1.18) 1.78 (1.00) 1.39 (0.37) 3.15 (0.86) 110.79 (29.81) 0.87 (0.19) 36 (41.4)
Q3 (21.80–28.37) ng/ml (n = 88) 24.87 (1.97) 59.50 (9.81) 26 (29.5) 4.48 (4.27) 25.84 (3.18) 86.64 (8.86) 8 (9.1) 14 (15.9) 57 (64.7) 136.65 (14.46) 83.64 (9.18) 7.81 (2.56) 6.29 (1.75) 5.27 (0.87) 2.14 (2.04) 1.50 (0.32) 2.95 (0.74) 109.89 (26.79) 0.90 (0.18) 27 (30.7)
Q4 (28.40–57.06) ng/ml (n = 87) 34.99 (6.05) 58.16 (9.29) 50 (57.5) 4.63 (4.36) 25.68 (3.40) 87.70 (8.76) 11 (12.6) 18 (20.7) 48 (55.2) 135.26 (18.20) 85.63 (9.18) 8.76 (4.23) 6.89 (1.66) 5.36 (0.99) 2.11 (1.61) 1.38 (0.41) 2.96 (0.79) 107.37 (29.05) 0.88 (0.20) 20 (23.0)
Fig. 1. a: Correlations of HbA1c with lg[25(OH)D] in men; b: Correlations of HbA1c with lg[25(OH)D] in women.
Fig. 2. a: Correlations of C-IMT with lg[25(OH)D] in men; b: Correlations of C-IMT with lg[25(OH)D] in women.
P-value for trend – 0.630 0.777 0.285 0.775 0.498 0.626 0.779 0.815 0.240 0.280 0.176 0.002 0.122 0.105 < 0.001 0.833 0.888 < 0.001 < 0.001
R.-h. Chen et al. / Annales d’Endocrinologie 75 (2014) 206–212 Table 4 Multivariate logistic regression analysis of the determinants of carotid plaque (R2 = 0.382).
Age Sex (male) LDL-C Current smoke Hypertension SBP HbA1c lg[25(OH)D]
OR(95%CI)
P-value
1.086 (1.049–1.124) 2.232 (1.249–3.988) 1.625 (1.162–2.274) 4.967 (1.872–13.183) 2.391 (1.311–4.363) 1.018 (1.001–1.037) 1.225 (1.036–1.339) 0.924 (0.893–0.955)
< 0.001 0.007 0.005 0.001 0.004 0.043 0.018 < 0.001
of serum 25-hydroxyvitamin D3 Levels with atherosclerosis in 1001 middle-aged and elderly men also showed a relatively mild OR[(95% CI): 0.972 (0.946–0.998), P = 0.032)] for 25(OH)D with carotid plaques [28]. Even though, since hypovitaminosis D is highly prevalent and low vitamin D level predicts higher risk of carotid atherosclerosis in our study as well as in some other studies we mentioned above, more attention should be paid to the biochemical mechanism and clinical effect of vitamin D on the prevention of macrovascular disease in patients with type 2 diabetes. In this study, we found 25(OH)D was inversely associated with C-IMT in men, but inversely correlated with HbA1c in women among patients with type 2 diabetes. Hao Y et al. [28] found that decreasing serum 25(OH)D3 levels were accompanied by increased C-IMT in Chinese middle-aged and elderly men. However, no study was performed on the association between 25(OH)D and IMT in diabetic women. Hartaigh et al. [29] found higher serum 25(OH)D levels were associated with better glycaemic status among patients undergoing coronary angiography. But they did not mention the difference between male and female. Study of Manickam et al. [30] showed that the 25(OH)D level is an independent determinant of HbA1c in African American men, but not in Caucasian American men, including men with and without diabetes, suggesting that the threshold of the vitamin D effect on HbA1c may be different between different races. Klop B et al. [31] found vitamin D3 probably increased postprandial arterial elasticity in both genders, but reduced postprandial leukocyte activation only in women. These findings indicate that hypovitaminosis D may affect male and female patients in different ways (multi-ways). Physiological mechanisms accounting for differences between men and women include the possibility that obesity varies by gender [30]. On the other hand, vitamin D insufficiency may contribute to hyperglycemia and obesity, both of which are risk factors of atherosclerosis, by affecting muscle strength and physical activity [32], and the process of energy metabolism might be different in men and women. More studies are needed to explore the potential different biological mechanisms in patients of different genders. Our study is limited by its cross-sectional design, and residual confounding and reverse causation are potential concerns, as in any cross-sectional study. Also, a one-time 25(OH)D measurement may not reflect lifetime vitamin D status. Besides, all the findings correspond to carotid atherosclerosis are not
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necessarily coronary atherosclerosis as well as cardiovascular events. Cohort studies are very necessary to figure out the association of vitamin D deficiency and future cardiovascular events in patients with type 2 diabetes in Shanghai. In addition, our results may not be generalizable to others living in different geographical latitudes and altitudes with differing sunlight exposure in China. The sample size in our study was relatively small, so it remains a possibility that a real association between 25(OH)D and carotid IMT among female patients, and glucose control among male patients exists and that our study was underpowered to detect it. In conclusion, our study indicates that a lower level of serum 25(OH)D in patients with type 2 diabetes is associated with carotid atherosclerosis. 25(OH)D may be associated with C-IMT, particularly in men, and glucose control in women. A reduction of serum 25(OH)D may independently predict subclinical atherosclerosis in diabetic patients. Results of our findings suggest the need for evaluation of the possible protective role of vitamin D in glucose control and the development of atherosclerosis in patients with type 2 diabetes in Shanghai. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements This work was supported by a joint research project of Shanghai health bureau (2010Y047, to R.C) and Shanghai Pudong New Area health bureau (PW2010B-6, PWRq2012-09, to R.C). X.J reviewed and edited the manuscript. R.C designed the study, wrote the manuscript, and researched data. Q.J performed all the carotid artery ultrasound. Z.G, P.G, B.Z, Z.Z, L.X, Y.Q, Y.Z researched data. References [1] Yang W, Lu J, Weng J, Jia W, Ji L, Xiao J, et al. Prevalence of diabetes among men and women in China. N Engl J Med 2010;362:1090–101. [2] Lin C-C, Li C-I, Hsiao C-Y, Liu C-S, Yang S-Y, Lee C-C, et al. Time trend analysis of the prevalence and incidence of diagnosed type 2 diabetes among adults in Taiwan from 2000 to 2007: a population-based study. BMC Public Health 2013;13:318. [3] Brun E, Nelson RG, Bennett PH, Imperatore G, Zoppini G, Verlato G, et al. Diabetes duration and cause-specific mortality in the Verona Diabetes Study. Diabetes Care 2000;23:1119–23. [4] Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229–34. [5] Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81. [6] Lu L, Yu Z, Pan A, Hu FB, Franco OH, Li H, et al. Plasma 25hydroxyvitamin D concentration and metabolic syndrome among middleaged and elderly Chinese individuals. Diabetes Care 2009;32:1278–83. [7] Lim S, Kim MJ, Choi SH, Shin CS, Park KS, Jang HC, et al. Association of vitamin D deficiency with incidence of type 2 diabetes in high-risk Asian subjects. Am J Clin Nutr 2013;97:524–30. [8] Wang L, Song Y, Manson JE, Pilz S, März W, Michaëlsson K, et al. Circulating 25-hydroxyvitamin D and risk of cardiovascular disease: a
212
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16] [17]
[18]
[19] [20]
R.-h. Chen et al. / Annales d’Endocrinologie 75 (2014) 206–212 meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes 2012;5:819–29. Reis JP, von Mühlen D, Michos ED, Miller ER, Appel LJ, Araneta MR, et al. Serum vitamin D, parathyroid hormone levels, and carotid atherosclerosis. Atherosclerosis 2009;207:585–90. Cheraghi N, Dai H, Raghuveer G. Vitamin D deficiency is associated with atherosclerosis-promoting risk factor clustering but not vascular damage in children. Med Sci Monit 2012;18:CR687–92. Michos ED, Streeten EA, Ryan KA, Rampersaud E, Peyser PA, Bielak LF, et al. Serum 25-hydroxyvitamin D levels are not associated with subclinical vascular disease or C-reactive protein in the old order Amish. Calcif Tissue Int 2009;84:195–202. Knox S, Welsh P, Bezlyak V, McConnachie A, Boulton E, Deans KA, et al. 25-hydroxyvitamin D is lower in deprived groups, but is not associated with carotid intima media thickness or plaques: results from pSoBid. Atherosclerosis 2012;223:437–41. Targher G, Bertolini L, Padovani R, Zenari L, Scala L, Cigolini M, et al. Serum 25-hydroxyvitamin D3 concentrations and carotid artery intimamedia thickness among type 2 diabetic patients. Clin Endocrinol (Oxf) 2006;65:593–7. Stein JH, Korcarz CE, Post WS. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: summary and discussion of the American Society of echocardiography consensus statement. Prev Cardiol 2009;12:34–8. Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of echocardiography carotid intima-media thickness task force endorsed by the Society for vascular medicine. J Am Soc Echocardiogr 2008;21:93–111. Li YC. Vitamin D regulation of the renin-angiotensin system. J Cell Biochem 2003;88:327–31. Chiu KC, Chu A, Go VLW, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta-cell dysfunction. Am J Clin Nutr 2004;79:820–5. Kayaniyil S, Retnakaran R, Harris SB, Vieth R, Knight JA, Gerstein HC, et al. Prospective associations of vitamin D with -cell function and glycemia: the PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study. Diabetes 2011;60:2947–53. Zittermann A. Vitamin D and disease prevention with special reference to cardiovascular disease. Prog Biophys Mol Biol 2006;92:39–48. Weng S, Felton SK, Bhandare S, Riek A, Butler B, Proctor BM, et al. 1,25(OH)2 vitamin D inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus. Circulation 2009;120:687–98.
[21] Jeevarethinam A, Venuraju S, Weymouth M, Atwal S, Lahiri A. Carotid intimal thickness and plaque predict prevalence and severity of coronary atherosclerosis: a pilot study. Angiology 2014. [22] Pursnani S, Diener-West M, Sharrett AR. The effect of aging on the association between coronary heart disease risk factors and carotid intima media thickness: an analysis of the atherosclerosis risk in communities (ARIC) cohort. Atherosclerosis 2014;233:441–6. [23] Kawamoto R, Katoh T, Kusunoki T, Ohtsuka N. Carotid atherosclerosis as a surrogate maker of cardiovascular disease in diabetic patients. ISRN Endocrinol 2013;2013:979481. [24] Alele JD, Luttrell LM, Hollis BW, Luttrell DK, Hunt KJ, VADT Study Group. Relationship between vitamin D status and incidence of vascular events in the veterans affairs diabetes trial. Atherosclerosis 2013;228:502–7. [25] Sachs MC, Brunzell JD, Cleary PA, Hoofnagle AN, Lachin JM, Molitch ME, et al. Circulating vitamin D metabolites and subclinical atherosclerosis in type 1 diabetes. Diabetes Care 2013. [26] Choi HS, Kim SH, Rhee Y, Cho MA, Lee EJ, Lim S-K. Serum parathyroid hormone is associated with carotid intima-media thickness in postmenopausal women. Int J Clin Pract 2008;62:1352–7. [27] Brøndum-Jacobsen P, Benn M, Jensen GB, Nordestgaard BG. 25hydroxyvitamin d levels and risk of ischemic heart disease, myocardial infarction, and early death: population-based study and meta-analyses of 18 and 17 studies. Arterioscler Thromb Vasc Biol 2012;32:2794– 802. [28] Hao Y, Ma X, Luo Y, Ni J, Dou J, Zhu J, et al. Additional role of serum 25-hydroxyvitamin D3 levels in atherosclerosis in Chinese middle-aged and elderly men. Clin Exp Pharmacol Physiol 2014. [29] O’Hartaigh B, Neil Thomas G, Silbernagel G, Bosch JA, Pilz S, Loerbroks A, et al. Association of 25-hydroxyvitamin D with type 2 diabetes among patients undergoing coronary angiography: cross-sectional findings from the LUdwigshafen Risk and Cardiovascular Health (LURIC) Study. Clin Endocrinol (Oxf) 2013;79:192–8. [30] Manickam B, Neagu V, Kukreja SC, Barengolts E. Relationship between glycated hemoglobin and circulating 25-hydroxyvitamin D concentration in African American and Caucasian American men. Endocr Pract 2013;19:73–80. [31] Klop B, van de Geijn G-J, Birnie E, Njo TL, Janssen HW, Jansen HG, et al. Vitamin D3 mediated effects on postprandial leukocyte activation and arterial stiffness in men and women. Eur J Clin Nutr 2014. [32] Muir SW, Montero-Odasso M. Effect of vitamin D supplementation on muscle strength, gait and balance in older adults: a systematic review and meta-analysis. J Am Geriatr Soc 2011;59:2291–300.
