|Year : 2018 | Volume
| Issue : 5 | Page : 678-682
Serum uric acid levels in Type 2 diabetes mellitus: Is there a linear relationship with severity of carotid atherosclerosis?
Shantan Venishetty1, Rama Bhat1, KV Rajagopal2
1 Department of Medicine, Kasturba Hospital, Manipal, Karnataka, India
2 Department of Radiodiagnosis, Kasturba Hospital, Manipal, Karnataka, India
|Date of Web Publication||18-Sep-2018|
“Sumedha,” Vidyaratna Nagar, 3rd Cross, Manipal - 576 104, Karnataka
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aims: The aim of this study was to correlate serum uric acid (SUA) levels and carotid intima-media thickness (CIMT) in patients with type 2 diabetes mellitus (DM). Settings and Design: This study was a cross-sectional observational study on 103 diabetic patients conducted from September 2015 to May 2017. Subjects and Methods: We screened 103 patients with type 2 DM between the ages of 30–65 years. SUA levels and the CIMT were measured. The patients were divided into quartiles based on uric acid level. The CIMT of the quartiles is compared and analyzed. Statistical Analysis Used: Chi-squared test, Analysis of Variance, and Pearson's correlation. Results: Uric acid levels were positively associated with CIMT (P = 0.001). The association remained significant after further adjustment for potential confounders. Strong correlation was found among them as depicted by correlation coefficient (r = 0.779). Conclusions: Carotid atherosclerosis as measured by IMT is associated with SUA levels in patients with type 2 DM.
Keywords: Atherosclerosis, intima-media thickness, serum uric acid
|How to cite this article:|
Venishetty S, Bhat R, Rajagopal K V. Serum uric acid levels in Type 2 diabetes mellitus: Is there a linear relationship with severity of carotid atherosclerosis?. Indian J Endocr Metab 2018;22:678-82
|How to cite this URL:|
Venishetty S, Bhat R, Rajagopal K V. Serum uric acid levels in Type 2 diabetes mellitus: Is there a linear relationship with severity of carotid atherosclerosis?. Indian J Endocr Metab [serial online] 2018 [cited 2019 Feb 20];22:678-82. Available from: http://www.ijem.in/text.asp?2018/22/5/678/241495
| Introduction|| |
In general population, it was suggested that one of the risk factor for cardiovascular disease (CVD) is hyperuricemia., However, still there was consideration of the fact that the association was confounded by certain established CVD risk factors., There is scarcity of data among the Indian population as most of the studies are from Japan and China and very few have studied the association in type 2 diabetes mellitus (DM) patients. In the modern era of 21st century, it was observed that hyperuricemia has a role in the development of metabolic syndrome (MetS), coronary artery disease, and DM. We studied the carotid intima-media thickness (CIMT) in diabetic patients and analyzed with the uric acid levels.
| Subjects and Methods|| |
A cross-sectional study was performed among 103 diabetic patients. The duration of the study was conducted from September 2015 to May 2017. The patients who are on uric acid lowering drugs such as allopurinol and febuxostat, patients on diuretics especially thiazides, patient who is not abstinent from alcohol consumption for the last 2 months, patients on drugs affecting serum uric acid (SUA) levels (salicylates, cyclosporine, ethambutol, pyrazinamide, and cytotoxic agents), patients with other comorbidities (cardiac disorders, renal disorders, and malignancies), and patients whose creatinine clearance is <60 ml/min/1.73 m2 were excluded from the study. The study was approved by the Ethics Committee of the Hospital, and written informed consents were obtained from all participants.
Each patient was given a questionnaire regarding the history of DM (duration and the present medications), history of hypertension (HTN), smoking and alcohol history, and family history of diabetes. Individual patient's glycated hemoglobin, fasting lipid profile (total cholesterol, triglycerides, and high-density lipoprotein cholesterol), and SUA level (measured using uricase/peroxidase calorimetric method) were measured. Estimated glomerular filtration rate was estimated using the modification of diet in renal disease equation.
Bilateral images of common carotid arteries, internal carotid artery, and carotid bulb is obtained by a lateral view by a single experienced radiologist who has expertise in cross-sectional imaging. The gap between the media-adventitia interface and lumen-intima interface is the IMT. The thickness was measured at 1 cm proximal to the dilatation of the carotid bulb. The mean of maximum IMT of both the common carotid artery is taken as the average CIMT.
The normally distributed data are expressed as the means ± standard deviation. The categorical variables are expressed in frequency and percentage. Analysis of Variance (ANOVA) is performed for continuous variables. For the categorical variables, multivariate linear regression analysis was performed for comparison according to the uric acid quartiles. Other categorical variables were analyzed using Chi-squared test. Potential confounding variables including gender, smoking, waist circumference, low-density lipoprotein cholesterol (LDL-C), alcohol, and HTN were controlled in the regression models. Correlation coefficients between uric acid and metabolic features were calculated by correlation analysis (Pearson's correlation). For data management and statistical analysis, SPSS version 23.0 (IBM, Chicago, Illinois, USA) for Windows was used. A value of P < 0.05 is considered statistically significant.
| Results|| |
Our study included 103 diabetic patients with age group between 30 years and 65 years of age. The baseline characteristics of the patients under study in mean or in percentage are shown in the [Table 1].
The mean age of the study patients was 54.5 ± 8.4 years with 65% being males and 40.8% having history of HTN. When analyzed mean uric acid levels among males was high compared to females, but was not statistically significant (P = 0.35).
The patients were divided into four quartiles based on the uric acid level. The baseline characteristics and medical characteristics of both genders as per the quartile are tabulated as given in [Table 2].
Association between serum uric acid and carotid atherosclerosis
The mean of CIMT in each quartile is calculated and tabulated [Table 3]. A bar diagram comparing mean CIMT in each quartile is depicted in [Figure 1]. A scatter plot was constructed with SUA levels on X-Axis and average CIMT (Average of the right and left CIMT) on Y-Axis [Figure 2].
|Figure 1: Bar diagram depicting mean carotid intima-media thickness in each quartile|
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|Figure 2: Scatter plot for the Serum Uric acid and Average carotid intima-media thickness|
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Significant differences between these four quartiles were found as analyzed by one-way ANOVA (P = 0.001). A Tukey posthoc test revealed that the CIMT was statistically significantly higher in the 1st quartile (0.07396 ± 0.0045) and 4th quartile (0.07396 ± 0.0045) (P = 0.001) compared to the 1st quartile (0.07396 ± 0.0045) and 2nd quartile (0.07626 ± 0.0058) (P = 0.643).
Multiple linear regression analysis was performed with CIMT and uric acid, HTN, LDL-C, sex, waist circumference, smoking, and alcohol intake. HTN (P = 0.003) and SUA (P = 0.001) were found to be statistically significant [Table 4].
|Table 4: Linear regression analysis of carotid intima-media thickness with other variables|
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Pearson's correlation analysis was performed to find the correlation between SUA and CIMT. A strong correlation for CIMT with SUA was obtained with correlation coefficient of r = 0.779 (with P = 0.001) which was statistically significant.
| Discussion|| |
Our study is a cross-sectional study, conducted at a tertiary care center. We enrolled 103 diabetic patients. It was found that there was a positive correlation between SUA levels and CIMT, and hence, to the carotid atherosclerosis.
The patients were divided into four quartiles, based on uric acid levels and compared. The rationale for using quartiles of uric acid is that in this descriptive study there are neither comparative groups nor controls. The values of uric acid levels were almost in the normal range and there were only few patients with high uric acid levels. Hence, quartiles based on uric acid levels were computed such that the mean CIMT can be compared among quartiles to find a correlation.
It was found that the mean CIMT in the last quartile (0.095 cm) was higher compared to the first quartile (0.074 cm) and this observation was statistically significant (P = 0.001).
The GREek Atorvastatin and Coronary heart disease Evaluation study, and the Losartan Intervention for Endpoint reduction in HTN study  have shown the possible causal relationship between SUA and cardiovascular risks.
In this study, 103 diabetic patients were studied in between the age groups of 30 years and 65 years. The mean age of the patients in the study is 54.5 ± 8.4 years. Similar study by Li et al., recruited Chinese patients (65.57 ± 11.70 years). A study by Ishizaka et al. studied Japanese patients (56.6 ± 10.4 years). The mean baseline values of the patients under study compared to similar studies is shown in [Table 5]. Ishizaka et al. published a similar study in 2005 among Japanese individuals, while Li et al. published a study similar to the study in 2011 among Chinese individuals.
|Table 5: Baseline characteristics of our study compared to similar studies|
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Uric acid levels are generally higher in males than in females. This is thought to be due to higher levels of estrogen in the plasma of females compared to males leading to higher renal clearance of urate by estrogen in females.
In this study, males made up to 65% while females were 35%. This is similar to the study by Ishizaka et al. The mean uric acid levels among males is 4.50 ± 0.21 mg/dL and among females is 4.08 ± 0.15 mg/dL. Although it was found that the uric acid levels in males are slightly higher than in females in the study, the finding was not statistically significant (P = 0.35).
For comparison among groups and to find an association between uric acid levels and CIMT, quartiles were computed based on uric acid levels. There were 27 patients grouped into first quartile and second quartile with uric acid levels ranging from 1.7 mg/dL to 3.3 mg/dL and 3.4 mg/dl to 4.1 mg/dl, respectively. About 25 patients were grouped into third quartile with uric acid levels ranging from 4.2 mg/dL to 5.2 mg/dL. Twenty-four patients were grouped into fourth quartile with uric acid levels above 5.3 mg/dL.
The mean CIMT in each uric acid quartile is calculated and compared. In this study, it is observed that the mean CIMT showed a gradual increase with each quartile. This implies that high uric acid level is seen with patients with high CIMT thereby representing higher degree of atherosclerosis. 0.074 cm in the 1st quartile, 0.076 cm in the 2nd quartile, 0.085 cm in the 3rd quartile, and 0.095 cm in the 4th quartile. Increasing level of uric acid although within the normal range seems to be associated with increase in the CIMT in a linear way.
ANOVA between the uric acid groups and CIMT was performed, and it was observed that the increase in mean CIMT with the increase in uric acid as per the quartile range was statistically significant (P = 0.001).
A posthoc Tukey test was performed among the quartile groups and it was observed that increase in mean CIMT among the 1st and 2nd quartile group is not statistically significant, but the difference in CIMT among the 1st quartile when compared to 3rd and 4th quartile is statistically significant. This signifies that there is an association of SUA with the CIMT (representing the carotid atherosclerosis) at higher levels of uric acid.
A multiple linear regression analysis was performed on CIMT with various variables [Table 4]. It was found that only HTN and SUA had a positive impact on CIMT while sex, history of smoking, waste circumference, and LDL-cholesterol had no effect on the CIMT.
Experimental studies have also shown the harmful effects of uric acid on vascular smooth muscle cells (VSMCs) apart from its damage to the endothelium. The entry of uric acid causes the proliferation of VSMCs through the mitogen-activated protein kinase pathway, stimulates the production of pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1), and enhances angiotensinogen mRNA expression and reactive oxygen species production in VSMCs.
SUA possesses oxidative properties by mediating the production of radicals that have pro-oxidant effect on LDL-C. Increased uric acid levels causes endothelial dysfunction and reduces the bioavailability of NO. It enters into the VSMCs by urate transporters and increased levels induces the proliferation of VSMC's. This causes thickening of the vessel wall or the increase in the IMT.
The possible association of increased uric acid levels and coronary heart disease and their independence had been analyzed in several previous studies. Some showed a positive association  and some did not., Most of the studies showed that the association was not independent. In alcohol abstainers, it was shown to have an independent association.
Pan et al. studied a population of 145 (n = 145), and after adjusting for age and sex, uric acid showed no significant correlation with carotid plaque. A total of 10,000 are included in the Atherosclerosis Risk in Communities Study and the possible associations between carotid atherosclerosis and uric acid were extensively studied.
Li et al. revealed a uric acid significantly correlated with carotid atherosclerosis (CIMT) (P = 0.02). The correlation coefficient was 0.07. Ishizaka et al. revealed a positive association between SUA, metabolic syndrome, and carotid plaque. However, when multivariate analysis was performed with adjustment of age, and smoking, the association was statistically significant only in men. For the presence of carotid plaque, it was found that uric acid is a risk factor in men without metabolic syndrome.
Kawamoto et al. revealed that uric acid had an independent association with carotid atherosclerosis in males without metabolic syndrome. Gomez-Marcos et al. revealed that there is no association between SUA levels and CIMT (P = 0.39), while Erdogen et al. showed a positive association (P = 0.002).
| Conclusions|| |
In conclusion, our data indicate that SUA levels are significantly associated with carotid atherosclerosis in patients with type 2 diabetes, even after adjustment for other potential confounders.
The study includes the subset of population which may not represent the entire population with respect to region or ethnicity. This study is a descriptive cross-sectional study with no control group. Even though there is a correlation found between SUA levels and CIMT, further studies to be carried out to establish uric acid as an independent risk factor for CIMT (atherosclerosis).
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Meisinger C, Koenig W, Baumert J, Döring A. Uric acid levels are associated with all-cause and cardiovascular disease mortality independent of systemic inflammation in men from the general population: The MONICA/KORA cohort study. Arterioscler Thromb Vasc Biol 2008;28:1186-92.
Verdecchia P, Schillaci G, Reboldi G, Santeusanio F, Porcellati C, Brunetti P, et al.
Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study. Hypertension 2000;36:1072-8.
Moriarity JT, Folsom AR, Iribarren C, Nieto FJ, Rosamond WD. Serum uric acid and risk of coronary heart disease: Atherosclerosis risk in communities (ARIC) study. Ann Epidemiol 2000;10:136-43.
Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, et al.
Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001;38:1101-6.
Nuki G, Simkin PA. A concise history of gout and hyperuricemia and their treatment. Arthritis Res Ther 2006;8 Suppl 1:S1.
Athyros VG, Mikhailidis DP, Liberopoulos EN, Kakafika AI, Karagiannis A, Papageorgiou AA, et al.
Effect of statin treatment on renal function and serum uric acid levels and their relation to vascular events in patients with coronary heart disease and metabolic syndrome: A subgroup analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. Nephrol Dial Transplant 2007;22:118-27.
Daskalopoulou SS, Athyros VG, Elisaf M, Mikhailidis D. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004;66:1714-5.
Li Q, Yang Z, Lu B, Wen J, Ye Z, Chen L, et al.
Serum uric acid level and its association with metabolic syndrome and carotid atherosclerosis in patients with type 2 diabetes. Cardiovasc Diabetol 2011;10:72.
Ishizaka N, Ishizaka Y, Toda E, Nagai R, Yamakado M. Association between serum uric acid, metabolic syndrome, and carotid atherosclerosis in Japanese individuals. Arterioscler Thromb Vasc Biol 2005;25:1038-44.
Antón FM, García Puig J, Ramos T, González P, Ordás J. Sex differences in uric acid metabolism in adults: Evidence for a lack of influence of estradiol-17 beta (E2) on the renal handling of urate. Metabolism 1986;35:343-8.
Rao GN, Corson MA, Berk BC. Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression. J Biol Chem 1991;266:8604-8.
Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T, et al.
Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension 2003;41:1287-93.
Corry DB, Eslami P, Yamamoto K, Nyby MD, Makino H, Tuck ML, et al.
Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system. J Hypertens 2008;26:269-75.
Kanellis J, Kang DH, editors. Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease. Seminars in Nephrology. Elsevier; 2005;25:39-42.
Freedman DS, Williamson DF, Gunter EW, Byers T. Relation of serum uric acid to mortality and ischemic heart disease. The NHANES I epidemiologic follow-up study. Am J Epidemiol 1995;141:637-44.
Brand FN, McGee DL, Kannel WB, Stokes J 3rd
, Castelli WP. Hyperuricemia as a risk factor of coronary heart disease: The Framingham Study. Am J Epidemiol 1985;121:11-8.
Waring WS, Adwani SH, Breukels O, Webb DJ, Maxwell SR. Hyperuricaemia does not impair cardiovascular function in healthy adults. Heart 2004;90:155-9.
Pan WH, Bai CH, Chen JR, Chiu HC. Associations between carotid atherosclerosis and high factor VIII activity, dyslipidemia, and hypertension. Stroke 1997;28:88-94.
Kawamoto R, Tomita H, Ohtsuka N, Inoue A, Kamitani A. Metabolic syndrome, diabetes and subclinical atherosclerosis as assessed by carotid intima-media thickness. J Atheroscler Thromb 2007;14:78-85.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]