600640

research-article2015

TAE0010.1177/2042018815600640Therapeutic Advances in Endocrinology and MetabolismN. Hamdy et al.

Therapeutic Advances in Endocrinology and Metabolism

Vitamin D as a risk factor for premature atherosclerosis in patients with type 2 diabetes Nehal Hamdy Al-Said, Nagwa Abd El Ghaffar Mohamed, Randa F. Salam and Mary Wadie Fawzy

Original Research

Ther Adv Endocrinol Metab 2015, Vol. 6(6) 249­–257 DOI: 10.1177/ 2042018815600640 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav

Abstract Background: Several cardiovascular risk factors have been recognized in patients with diabetes and vitamin D deficiency is emerging as a new risk. The aim of this study was to determine the effect of vitamin D deficiency on the incidence of premature atherosclerosis in patients with type 2 diabetes. Methods: A total of 78 patients with type 2 diabetes were subjected to history taking, physical examination, fasting glucose level, homeostasis model assessment of insulin resistance, lipid profile, 25(OH) vitamin D measurement, and carotid Doppler. Results: Patients with normal carotid intima-media thickness (CIMT) had sufficient vitamin D. Of those with increased CIMT 23.1% had insufficient vitamin D while 76.9% had sufficient vitamin D (six patients had plaques, one of them had vitamin D insufficiency, and the other five patients had sufficient vitamin D). There was a statistically significant difference in the serum level of vitamin D between patients with increased CIMT, and those with normal intima, with a decreased level in the first group. There was a significant negative correlation between vitamin D and fasting blood glucose. There was a statistically significant correlation in left CIMT between the vitamin D sufficiency group and the vitamin D insufficiency group, with higher values in the second group. There was no statistically significant difference in serum cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol in patients with increased CIMT and those with normal intima. Conclusions: Decreased vitamin D levels in patients with diabetes lead to increased CIMT. The absence of a statistically significance difference in lipid profile between increased and normal CIMT groups raises the possibility of underlying causes for atherosclerosis in patients with diabetes other than dyslipidemia.

Keywords:  diabetes, vitamin D, atherosclerosis

Introduction It is well known that inflammation plays a key role in the development of atherosclerosis. Inflammatory cells, mainly macrophages and T lymphocytes, produce a wide range of inflammatory cytokines in atherosclerotic lesions, which are critically important in the progression of atherosclerosis-related cardiovascular disease (CVD) [Kamycheva et  al. 2013]. Vitamin D has recently been found to play an important role in the modulation of the immune/ inflammation system by regulating the production of inflammatory cytokines and inhibiting the

proliferation of proinflammatory cells, both of which are crucial for the pathogenesis of inflammatory diseases [Kamycheva et al. 2013]. Vitamin D deficiency is associated with excess mortality [Melamed et al. 2008]. It is becoming increasingly clear that vitamin D has a much broader range of actions in the human body in addition to its wellknown effects on calcium homeostasis and bone metabolism. There is accumulating evidence that vitamin D deficiency has important extra skeletal effects, including effects on the cardiovascular

Correspondence to: Mary Wadie Fawzy, MD Department of Internal Medicine and Vascular Laboratory, Cairo University, 18th Street el Sherbieny Street, Dokki, Giza, Egypt [email protected] Nehal Hamdy Al-Said, MD Randa F. Salam, MD Department of Internal Medicine and Endocrinology, Cairo University, Cairo, Egypt Nagwa Abd El Ghaffar Mohamed, MD Department of Clinical and Chemical Pathology, National Research Center, Cairo, Egypt

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Therapeutic Advances in Endocrinology and Metabolism 6(6) system [O’Leary et al. 2002]. Several clinical studies have reported a high prevalence of vitamin D deficiency in patients with peripheral arterial disease, coronary artery disease, and stroke [Pearce and Cheetham, 2010], as well as the association of vitamin D deficiency with cardiovascular mortality [Melamed et al. 2008]. Furthermore, low vitamin D status is related to major cardiovascular risk factors, such as hypertension, obesity, and diabetes mellitus. Currently there is a lack of information on the associations between vitamin D status and carotid artery intima-media thickness (CIMT) (a reliable marker of preclinical, generalized atherosclerosis) [O’Leary and Polak, 2002]. Hypovitaminosis D is a novel risk factor for CVD [Brewer et  al. 2011]. There is now accumulating experimental and clinical evidence suggesting both associative relationships and mechanisms for biological plausibility (i.e. to establish a cause-andeffect relationship between a biological factor and a particular disease or adverse event). Patients with type2 diabetes mellitus are recognized to be at an increased risk of atherosclerotic diseases, including CVD [Scragg et al. 2004]. The risk of CVD mortality in patients with type 2 diabetes is more than double compared with that in age-matched subjects. Stroke events and all manifestations of coronary heart disease, myocardial infarction, sudden death, and angina pectoris are at least twofold more common in patients with type 2 diabetes than in nondiabetic individuals [Melamed et al. 2008]. The measurement of CIMT is an accepted surrogate marker of atherosclerosis. Over the years, clinical trials have provided outcomes that support the role of CIMT measurements for predicting cardiovascular events (i.e. the thicker the CIMT, the higher the rate of myocardial infarction or stroke) [Pearce and Cheetham, 2010]. Vitamin D is crucial not only in maintaining bone strength, but research also suggests it plays a role in immune system functioning, cancer prevention, glucose and lipid metabolism, and cardiovascular health. Recently, many studies have reported inverse associations between serum 25(OH) vitamin D levels and the risk of a variety of diseases, including diabetes mellitus, CVD, cancer, autoimmune diseases, infections, or cognitive decline. Clinically, vitamin D has been shown to be linked with glucose and insulin homeostasis [Pearce and Cheetham, 2010]. It is well known that the endothelium is the key vessel-wall component in the initiation of the

atherogenic process. Its possible role in the later stages has been strongly suggested [Vanhoutte, 1997]. Studies revealed that endothelial cells (ECs) express vitamin D receptors (VDRs) and have the ability to synthesize calcitriol (1a,25(OH)2D3) because they express 1a-hydroxylase [Merke et al. 1989]. The coexistence of these two crucial elements of vitamin D metabolism strengthened the hypothesis of an autocrine/intracrine mechanism of vitamin D action as a modulator of endothelial functions [Zehnder et al. 2002]. Vitamin D exerts protective effects on endothelial activation/dysfunction, an inflammatory process that precedes atherosclerosis, through several mechanisms both genomic and nongenomic. Among the main alterations ascribable to endothelial dysfunction are the reduced availability of nitric oxide and the increased production of reactive oxygen species [Vanhoutte, 1997]. Moreover, vitamin D protected ECs against hydrogen peroxide oxidative stress, counteracting superoxide anion generation and apoptosis, and blocking the extrinsic caspase cascade by positively controlling the level of phospho-active, extracellular, signal-regulated kinases. Exploring in vitro the 1a,25(OH)2D downstream effector, Haussler and colleagues found that 1a,25(OH)2D upregulated SIRT-1 expression in human umbilical vein ECs and reverted the SIRT-1 downregulation induced by hydrogen peroxide.[Haussler et al. 2011]. Vitamin D also appears to be implicated in the modulation of vascular tone through the regulation of the release of vasoconstrictor metabolites of arachidonic acid called endothelium-derived contracting factors [Vanhoutte et  al. 2005]. The release of endothelium-derived contracting factors occurs via a calcium-dependent process in which the calcium influx activates phospholipase A2, which in turn converts the membrane phospholipids to arachidonic acid. Vitamin D acutely modulates vascular tone by reducing calcium influx into the ECs, hence decreasing the production of endothelium-derived contracting factors [Wong et al. 2008]. There is association between vitamin D status and CIMT among individuals with type 2 diabetes, as concluded in Kamycheva et al, 2013 study who estimate the prevalence of hypovitaminosis

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NH Al-Said, N Abd El Ghaffar et al. D and assess the relationship between serum 25(OH) vitamin D concentrations and CIMT in a representative sample of outpatients with type 2 diabetes, and they concluded that clarification of these relationships may be of clinical importance in planning preventive and therapeutic therapies. Methods A total of 78 patients with type 2 diabetes who attended the diabetes and endocrinology clinic at the Kasr El Aini hospital in Cairo were selected for this cross-sectional study. Those with a recent history of acute illness or advanced chronic liver or renal disease, and those taking any medications known to affect vitamin D metabolism (e.g. antiepileptic drugs, glucocorticoids) were excluded. Local medical ethical committee approval was obtained and informed consent was taken from all patients. A full medical history, complete physical examination, anthropometric measurements (e.g. body mass index, waist circumference) were carried out on all patients. Laboratory investigations, including fasting blood glucose, homeostasis model assessment of insulin resistance (HOMA-IR), serum cholesterol, triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL), serum 25(OH) vitamin D measurement, and fasting serum insulin were carried out. Fasting (12–16 h) 3 ml venous blood samples were taken from each participant, left to clot, the serum separated by centrifugation at 3000 × g for 10 min, and the separated serum then stored at −20ºC for the determination of fasting blood glucose (immediate determination), total cholesterol, triglycerides, insulin, and vitamin D. The determination of fasting blood glucose, serum cholesterol and serum triglycerides were carried out on a Hitachi 912 chemistry analyzer (Roche Diagnostics GmbH, D-68298 Mannheim, Germany) by colorimetric techniques. For the determination of HDL-cholesterol (HDLc), phosphotungstic acid and magnesium ions were used for precipitating all lipoproteins except the HDL fraction present in the supernatant and measured by auto-analyzer. LDL-cholesterol (LDLc) was measured by the Friedewald formula [Friedewald et al. 1972]. Fasting serum insulin was determined using radioimmunoassay [Perez-Fontan et al.,2004]. Insulin

Figure 1.  Doppler machine.

resistance was calculated as HOMA-IR using the following equation: HOMA-IR = fasting blood glucose (mmol/l) × fasting serum insulin (µIU/ ml)/405 [Wallace et al. 2004]. Vitamin D (25(OH) vitamin D) was determined using electro-chemiluminescence binding assay performed on a Cobas e411 immunoassay analyzer (Roche Diagnostics GmbH). Vitamin D deficiency was defined as ⩽20 ng/ml while vitamin D insufficiency is recognized as 21–29 ng/ml. The recommended level for vitamin D is ⩾30 ng/ml [Emmen et al. 2012]. Imaging procedure All patients were subjected to an imaging procedure in the form of a carotid Doppler to measure the IMT of the distal common carotid (Figures 1 and 2), to detect any atherosclerotic plaques if present, and the peak systolic velocity, end-diastolic velocity, and resistive index of the internal carotid artery by carotid ultrasound. B (brightness)-mode gray scale, color, and spectral Doppler techniques were used to investigate the carotid arteries according to the standardized protocol. The same operator interpreted all studies in a blind fashion, and the same ultrasound unit HD 5000 was used, with a linear probe (7.5 MHz) for scanning all participants.

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Therapeutic Advances in Endocrinology and Metabolism 6(6) Table 1.  Mean and standard deviation of different demographic data and laboratory findings of patients.

Figure 2.  Carotid intima-media thickness.

Statistical methods Data were coded and entered using the statistical package SPSS version 21. Data were summarized using the mean and standard deviation for quantitative variables, and frequencies (number of cases) and relative frequencies (percentages) for categorical data. Comparisons between groups were performed using the unpaired t-test for quantitative variables and the chi-square test was used for comparing categorical data. Fisher’s exact test was used when the expected frequency was less than 5. Pearson correlation coefficient was used to test for linear relations between quantitative variables. p values less than 0.05 were considered to be statistically significant. Results The mean age of our patients included in the study was 48.221 ± 8.429 years, the mean body mass index was 33.115 ± 5.236 kg/m2, mean level of vitamin D was 25.094 ± 3.537, mean fasting blood sugar was 10.23 ± 2.62 mmol/l, mean HOMA-IR was 6.14 ± 2.696, mean serum cholesterol was 5.14 ± 0.91 mmol/l, mean serum triglyceride was 1.16 ± 0.40 mmol/l, mean LDLc was 3.47 ± 0.81 mmol/l, mean HDLc was 1.04 ± 0.21 mmol/l (Table 1).

Parameters

All patients

Age (years) Weight (kg) Body mass index (kg/m2) Vitamin D (ng/ml) Fasting blood glucose (mmol/l) Homeostasis model assessment of insulin resistance Cholesterol (mmol/l) Triglycerides (mmol/l) High-density lipoprotein (mmol/l) Low-density lipoprotein (mmol/l)

48.221 ± 8.429 84.307 ± 14.074 33.115 ± 5.236 25.094 ± 3.537 10.23 ± 2.62 6.14 ± 2.696 5.14 ± 0.91 1.16 ± 0.40 1.04 ± 0.21 3.47 ± 0.81

According to carotid duplex patients were classified into diabetic with normal CIMT (n = 26) and diabetic with increased CIMT. There was a statistically significant difference in systolic blood pressure and diastolic blood pressure between patients with increased CIMT and those with normal intima, with the increased level in the first group having a p value less than 0.05. There was a statistically significant difference in the serum level of vitamin D between patients with increased CIMT and those with a normal intima, with the decreased level in the first group having a p value less than 0.05. There was no statistically significant difference in serum cholesterol, triglyceride, HDLc, LDLc, HOMA-IR, and body mass index in patients with increased CIMT and those with normal intima (Table 2). There was a statistically significant correlation in HOMA-IR between the vitamin D sufficiency group and the vitamin D insufficiency group, with lower values in the second group (Table 3). There was no statistically significant difference in serum cholesterol, serum triglyceride, LDLc, HDLc, and systolic and diastolic blood pressure between the vitamin D sufficiency group and the vitamin D insufficiency group, with higher values in the second group (Table 3). There was a statistically significant correlation in left CIMT between the vitamin D sufficiency group and the vitamin D insufficiency group, with higher values in the second group (Table 4).

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NH Al-Said, N Abd El Ghaffar et al. Table 2.  Comparison between different parameters in patients with diabetes with increased and normal carotid intima media thickness. Groups Parameters Age (years) Duration of diabetes (years) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Weight (kg) Body mass index (kg/m2) Vitamin D (ng/ml) Fasting blood glucose (mmol/l) Homeostasis model assessment of insulin resistance Cholesterol (mmol/l) Triglyceride (mmol/l) High-density lipoprotein (mmol/l) Low-density lipoprotein (mmol/l)

Patients with diabetes with normal carotid intima media thickness (n = 26)

Patients with diabetes with increased carotid intima media thickness (n = 52)

p value

46.12 ± 9.67 5.92 ± 3.33 126.15 ± 14.72 83 ± 12 84.69 ± 16.02 32.96 ± 5.44 26.17 ± 3.64 10.53 ± 2.69 6.29 ± 2.39

50.33 ± 7.53 8.12 ± 3.03 139.04 ± 15.63 90 ± 11 83.92 ± 11.08 33.27 ± 5.00 24.02 ± 3.84 9.93 ± 2.56 5.90 ± 2.80

0.059 0.005 0.001 0.018 0.805 0.804 0.020 0.343 0.537

5.19 ± 1.02 1.07 ± 0.34 1.05 ± 0.21

5.10 ± 0.89 1.26 ± 0.69 1.04 ± 0.21

3.54 ± 1.05

3.41 ± 0.73

0.676 0.189 0.746 0.527

There was a significant correlation between vitamin D levels and fasting blood glucose level, and also a significant correlation between right CIMT and serum cholesterol and LDLc levels (Table 5). Discussion Atherosclerosis is the cause of a majority of cardiovascular events, and atherosclerosis is accelerated by diabetes and the metabolic syndrome. Many risk factors are associated with the metabolic syndrome and help explain the increased CVD in that condition [Reilly and Rader, 2003]. As the metabolic syndrome occurs in most people with type 2 diabetes, its presence likely accounts for most of the increased incidence of CVD in type 2 diabetes. However, the presence of diabetes increases the risk of CVD beyond that seen with the metabolic syndrome alone [Alexander et al. 2003]. Vitamin D deficiency has been linked to an increased risk of hypertension, diabetes, congestive heart failure, peripheral arterial disease, myocardial infarction, stroke, and related mortality, even after adjustment for traditional cardiovascular risk factors. Accumulating evidence from experimental, clinical, and epidemiological studies suggests that vitamin D may also be associated with several indices of vascular function, including the development and progression of atherosclerotic CVD [Brewer et al. 2011].

Hypovitaminosis D is highly prevalent in type 2 diabetes and suggests that hypovitaminosis D might be an underestimated, novel risk factor for CVD among adults with type 2 diabetes [Scragg et al. 2004]. Vitamin D deficiency plays a role in the promotion of atherosclerosis. However, it is not known whether this is a direct effect of vitamin D on the arterial wall and/or the result of a vitamin D deficiency-associated increase in established cardiovascular risk factors. It is also unclear whether the severity of arterial disease is related to the severity of vitamin D deficiency [Wang et al. 2008]. Carotid atherosclerosis is a progressive, multifactorial artery disease associated with high risks of morbidity and mortality [Allison et  al. 2012]. Subclinical carotid atherosclerosis is an acknowledged challenge in primary stroke prevention. Several underlying environmental and modifiable factors, such as increased, elevated systolic blood pressure, dyslipidemia, smoking, and increased body mass index, play a significant role in the progression of the atherogenic process [Jashari et al. 2013]. CIMT and plaque assessment by cervical ultrasonography is a noninvasive, feasible, and accurate method for detecting asymptomatic carotid atherosclerosis [Touboul et al. 2012]. We studied 78 patients with type 2 diabetes to detect the risk of vitamin D deficiency on atherosclerosis. CIMT measurement was carried out as

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Therapeutic Advances in Endocrinology and Metabolism 6(6) Table 3.  Comparison of different parameters between sufficient and insufficient vitamin D. Vitamin D status

p value



Insufficiency

Sufficiency



Mean

Standard deviation

Mean

Standard deviation

Age (years) Diabetes duration (years) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Weight (kg) Body mass index (kg/m2) Vitamin D (ng/ml) Fasting blood glucose (mmol/l) Homeostasis model assessment of insulin resistance Cholesterol (mmol/l) Triglyceride (mmol/l) High-density lipoprotein (mmol/l) Low-density lipoprotein (mmol/l)

51.00 8.50 139.17 89 84.00 33.83 18.26 10.86 4.86

9.20 1.83 13.79 8 14.93 5.47 1.40 2.61 1.11

48.55 7.18 133.94 88 84.21 33.05 25.91 10.00 6.24

8.36 3.45 16.81 12 12.55 5.09 2.90 2.60 2.81

0.360 0.203 0.313 0.587 0.958 0.627 < 0.001 0.296 0.005

4.93 1.06 1.07 3.53

0.82 0.51 0.19 0.65

5.16 1.22 1.04 3.44

0.95 0.62 0.22 0.88

0.418 0.391 0.611 0.748

Statistical significant difference regarding vitamin D in the sufficient and insufficient groups (p = < 0.001).

Table 4.  Comparison between Doppler findings in both the vitamin D sufficiency group and the vitamin D insufficiency group. Vitamin D status

p value



Insufficiency



Mean

Standard deviation

Mean

Standard deviation

Right intima Right peak systolic velocity Right end-diastolic velocity Right resistive index Left intima Left peak systolic velocity Left end-diastolic velocity Left resistive index

0.10 85.12 28.43 0.67 0.10 96.09 33.67 0.67

0.01 24.37 10.21 0.07 0.01 15.36 11.38 0.07

0.10 80.88 29.54 0.63 0.09 85.29 31.58 0.73

0.10 22.63 10.03 0.07 0.02 24.68 10.75 0.73

an early marker of atherosclerosis. According to carotid duplex patients were classified into those with normal CIMT (n = 26) with sufficient vitamin D and increased CIMT (n = 52; 12 insufficient vitamin D, 40 sufficient vitamin D). No cases of vitamin D deficiency were found in spite of long history of diabetes. We found a nonsignificant negative correlation between the right intima media and vitamin D (r = −0.003, p = 0.981), in agreement with Michos and colleagues [Michos

Sufficiency

0.953 0.557 0.726 0.159 0.006 0.148 0.541 0.747

et al. 2009], Pilz and colleagues [Pilz et al. 2009], Richart and colleagues [Richart et  al. 2011], Shikuma and colleagues [Shikuma et  al. 2012], and Kamycheva and colleagues [Kamycheva et al. 2013]. However, Targher and colleagues [Targher et al. 2006], Reis and colleagues [Reis et al. 2009], Hajas and colleagues [Hajas et  al. 2011], Ross and colleagues [Ross et al. 2011], and Sypniewska and colleagues [Sypniewska et al. 2014] showed a linear correlation between vitamin D and CIMT.

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NH Al-Said, N Abd El Ghaffar et al. Table 5.  Correlation between vitamin D level, carotid intima-media thickness and different parameters of the patients.

Age

Systolic blood pressure

Diastolic blood pressure Weight

Body mass index

Vitamin D

Fasting blood glucose

Homeostasis model assessment of insulin resistance Cholesterol

Triglyceride

High-density lipoprotein Low-density lipoprotein

Right intima

Left intima

r p value n r p value n r p value N r p value n r p value n r p value n r p value n r p value n r p value n r p value n r p value n r p value n r p value n r p value n

Vitamin D

Right intima

Left intima

0.076 0.509 78 −0.092 0.421 78 −0.100 0.385 78 −0.134 0.243 78 −0.151 0.187 78 1

0.187 0.101 78 0.160 0.161 78 0.155 0.175 78 0.108 0.345 78 −0.047 0.681 78 −0.003 0.981 78 −0.154 0.178 78 0.066 0.568 78 −0.340** 0.002 78 0.064 0.576 78 −0.178 0.119 78 −0.342** 0.002 78 1

0.261* 0.021 78 0.191 0.094 78 0.116 0.314 78 0.043 0.711 78 0.082 0.473 78 −0.154 0.178 78 −0.155 0.174 78 0.009 0.937 78 −0.081 0.481 78 0.101 0.380 78 −0.063 0.583 78 −0.107 0.351 78 0.169 0.138 78 1 78 78

78 −0.415** 0.000 78 0.051 0.658 78 −0.044 0.703 78 −0.025 0.830 78 −0.252* 0.026 78 −0.059 0.608 −0.003 0.981 78 −0.154 0.178 78

These studies were not considered conclusive at all, due to limitations in study design and the different compounds administered. Poor stratification by age, race, geographic position, physical activity, and sunlight exposure were the main

78 0.169 0.138 78

confounding factors, in addition to the small sample size of cohorts. Moreover, the current definitions of the optimal level of vitamin D in humans are bone-driven and not assessed from a cardiovascular point of view. In addition, the different

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Therapeutic Advances in Endocrinology and Metabolism 6(6) compounds used for vitamin D supplementation (comprising both inactive forms of vitamin D and direct VDR agonists) may affect the reliability of these results. Conclusion Low serum 25(OH) vitamin D has no consistent association with mean CIMT. Thus it could not predict subclinical atherosclerosis in patients with diabetes. The contribution of the local activated vitamin D system within atherosclerotic plaque has not yet been appropriately investigated. Therefore, both basic research studies and clinical trials are needed for better elucidating the therapeutic and pathophysiological role of vitamin D in atherogenesis and CVD. Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. Declaration of Conflicting Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Vitamin D as a risk factor for premature atherosclerosis in patients with type 2 diabetes.

Several cardiovascular risk factors have been recognized in patients with diabetes and vitamin D deficiency is emerging as a new risk. The aim of this...
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