Journal of Pharmacy And Bioallied Sciences

ORIGINAL ARTICLE
Year
: 2019  |  Volume : 11  |  Issue : 2  |  Page : 127--132

Vitamin D and elevated serum uric acid as novel predictors and prognostic markers for type 2 diabetes mellitus


Abdulbari Bener1, Abdulla O A A Al-Hamaq2, Mustafa Öztürk3, Ihab Tewfik4,  
1 Department of Biostatistics and Medical Informatics, Cerrahpaşa Faculty of Medicine, Istanbul University, Istanbul, Turkey; Department of Evidence for Population Health Unit, School of Epidemiology and Health Sciences, The University of Manchester, Manchester, United Kingdom; Department of Endocrinology, International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
2 Qatar Diabetes Association, Qatar Foundation, Doha, Qatar
3 Department of Endocrinology, International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
4 Division of Food, Nutrition and Public Health, University of Westminster, London, United Kingdom

Correspondence Address:
Prof. Abdulbari Bener
Department of Biostatistics and Medical Informatics, Cerrahpaşa Faculty of Medicine, Istanbul University, 34098 Cerrahpaşa-Istanbul
Turkey

Abstract

Aim: To ascertain the active role of uric acid and vitamin D as potential biomarkers for impaired glucose metabolism among people living with type 2 diabetes mellitus (T2DM) in Turkish community. Subjects and Methods: This study was based on 680 patients with T2DM and 680 healthy subjects aged between 25 and 70 years, who visited the diabetes and endocrinology department of Istanbul Mega Medipol University Teaching Hospital, Istanbul, Turkey, during January 2016 to April 2018. The investigated biochemical indices included lipid profiles (low-density lipoprotein [LDL], high-density lipoprotein, total cholesterol, and triglyceride [TG]), uric acid, blood pressure (BP), serum creatinine, glycosylated hemoglobin (HbA1c), thyroid-stimulating hormone (TSH), postprandial glucose, and any related comorbidities. Results: This study reported significant differences between family history duration of patients with T2DM of ≤5 and >5 years when compared to that of control subjects with respect to body mass index (BMI), smoking habit, sheesha smoking, income, family history of metabolic syndrome, hypertension, coronary heart disease, and nephropathy. Similarly, significant differences were found between patients with T2DM (with family history T2DM duration of less than 5 years and more than 5 years in contrast to healthy subjects’ level of LDL, TG, fasting blood glucose, HbA1c, systolic BP (SBP), bilirubin, albumin, magnesium, potassium, calcium, number of sleeping hours, and TSH. We uncovered the correlation between serum uric acid level with the clinical biochemical indices related to T2DM: serum calcium (r = 0.336), magnesium (r = 0.272), potassium (r = 0.205), HbA1c (r = 0.638), fasting blood glucose (P = 0.486), bilirubin (r = 0.251), albumin (r = 0.285), LDL (r = 0.322), TG (r = 0.434), diastolic BP (DBP) (r = 0.392), SBP (r = 0.344), BMI (r = 0.482), waist circumference (WC) (r = 0.366), age (r = 0.217), number of sleeping hours (r = 0.275), and TSH (r = 0.445). Multivariate stepwise logistic regression showed that variables, such as serum vitamin D, uric acid, TSH, HbA1c, DBP, WC, BMI, and SBP, were considered at higher risk as significant (P < 0.001) predictors for T2DM. Conclusion: The results suggest strong positive correlation between serum uric acid level with BP (SBP and DBP), age, BMI, and WC among patients with T2DM. This study ascertains that an increase in uric acid level may be due to elevated level of HbA1c, metabolic syndrome, diabetes, obesity, and/or hypertension.



How to cite this article:
Bener A, Al-Hamaq AO, Öztürk M, Tewfik I. Vitamin D and elevated serum uric acid as novel predictors and prognostic markers for type 2 diabetes mellitus.J Pharm Bioall Sci 2019;11:127-132


How to cite this URL:
Bener A, Al-Hamaq AO, Öztürk M, Tewfik I. Vitamin D and elevated serum uric acid as novel predictors and prognostic markers for type 2 diabetes mellitus. J Pharm Bioall Sci [serial online] 2019 [cited 2019 Jun 27 ];11:127-132
Available from: http://www.jpbsonline.org/text.asp?2019/11/2/127/257058


Full Text



 Introduction



Type 2 diabetes mellitus (T2DM) with its comorbidities and mortality poses a significant burden on health-care expenditure. Substantial epidemiological studies suggest the pivotal role of serum uric acid as independent risk factor of cardiovascular disease (CVD), particularly in patients with hypertension and DM.[1],[2] T2DM is also a prime risk factor for CVD,[3],[4] which is the leading cause of death in Western countries.[3],[4],[5] Several modifiable risk factors, for example, diet, physical activity level, and sleep duration, can reduce the incidence of T2DM among at-risk individuals.[2] Several prospective studies have documented the impact of elevated serum uric acid level on the development of T2DM, metabolic syndrome,[2] hypertension,[3] and CVD.[4] ’Similarly, it has been confirmed that serum uric acid is a probable risk factor for developing DM,[6],[7],[8] metabolic syndrome,[8],[9] hypertension, stroke,[9],[10] and CVDs.[11] The value of elevated levels of uric acid in serum as risk factor for DM development is still under scrutiny. More recent studies have shown that uric acid levels are higher in subjects with prediabetes and early T2DM than that in healthy controls.[8],[9] Furthermore, an elevated serum uric acid level was found to increase the chances for developing T2DM in individuals with impaired glucose tolerance.[10] An elevated uric acid level, as reported, often precedes the development of obesity,[9] hyperinsulinemia,[10],[11],[12] and diabetes.[13],[14],[15] In addition, uric acid has been implicated in the initiation of metabolic syndrome[16] and hypertension.[17]

The aim of the study was to examine the potential role of uric acid as biomarker for impaired glucose metabolism and diabetes in Turkish population.

 Subjects and Methods



This study was based on 680 patients with T2DM and 680 healthy subjects aged between 25 and 70 years, who visited the diabetes and endocrinology department of Istanbul Mega Medipol University Teaching Hospital, Istanbul, Turkey, during January 2016 to April 2018.

Laboratory measurements

People living with T2DM were considered as “case” patients if they had a history of DM and were taking any oral diabetes medications for 3 years.[18],[19],[20] These “case” subjects were investigated for their lipid profile (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], triglyceride [TG]), glycosylated hemoglobin (HbA1c), postprandial glucose, blood pressure (BP), serum creatinine, thyroid, and presence of any related medical comorbidities. On the contrary, “healthy” subjects were the ones who were not taking any DM medications and whose HbA1c levels were less than 6.5% and their fasting blood glucose levels were less than 7.0 mmol/L (126mg/dL), which were confirmed from their medical records.

Statistical analysis

Student’s t-test was conducted to reveal if any significant difference exists between mean values of two continuous variables. One-way analysis of variance (ANOVA) was used for comparison of more than two mean values. Fisher’s exact test (two-tailed) and chi-square test were used to show differences in proportions of categorical variables between two or more groups. Multivariate logistic regression analysis was used to estimate the associated risk factors for T2DM. Pearson’s correlation coefficient test was used between two continues variables (P < 0.05 was regarded as the cutoff value for significance).

 Results



Sociodemographic and clinical characteristics of investigated cases/patients with T2DM and control subjects are shown in [Table 1]. The findings showed significant differences between patients with T2DM with less than 5 years and more than 5 years of T2DM history when compared with control subjects with respect to their body mass index (BMI) (kg/m2), smoking habit, sheesha smoking, income, family history of metabolic syndrome, hypertension, coronary heart disease (CHD), and nephropathy.{Table 1}

[Table 2] shows the baseline values of biochemical indices among patients with T2DM versus control subjects. Significant differences were reported between patients with T2DM (with less than 5 years and more than 5 years of T2DM history) when compared to control subjects with respect to the values of their calcium (P < 0.001), magnesium (P < 0.001), potassium (P < 0.001), HbA1c (P < 0.001), fasting blood glucose (P < 0.001), TG (P < 0.001), LDL (P = 0.008), bilirubin (P = 0.015), systolic BP (SBP) (P = 0.009), albumin (P < 0.001), number of sleeping hours (P < 0.001), and thyroid-stimulating hormone (TSH) (P < 0.001).{Table 2}

[Table 3] shows a correlation between serum uric acid level with the clinical biochemical indices related to T2DM with serum calcium (r = 0.336), magnesium (r = 0.272), potassium (r = 0.205), fasting blood glucose (r = 0.486), TG (r = 0.434), HbA1c (r = 0.638), LDL (r = 0.322), bilirubin (r = 0.251), albumin (r = 0.285), diastolic BP (DBP) (r = 0.392), SBP (r = 0.344), BMI (r = 0.482), waist circumference (WC) (r = 0.366), age (r = 0.217), number of sleeping hours (r = 0.275), and TSH (r = 0.445).{Table 3}

[Table 4] shows multivariable stepwise logistic regression analysis of independent predictors for the presence of diabetes. Serum vitamin D (mmol/L) (odds ratio [OR], 3.38, 95% confidence interval [CI], 1.60–5.80; P < 0.001), uric acid (mmol/L) (OR, 3.24, 95% CI, 1.84–4.53; P < 0.001), TSH (mIU/L) (OR, 3.11, 95% CI, 2.12–4.40; P < 0.001), HbA1c (OR, 2.95, 95% CI, 1.77–4.32; P < 0.001), DBP (OR, 2.88, 95% CI, 2.13–3.91; P < 0.001), WC (cm) (OR, 2.61, 95% CI, 1.72–4.44; P < 0.001), BMI (OR, 2.39, 95% CI, 1.68–4.39; P = 0.003), and SBP (mm Hg) (OR, 1.78, 95% CI, 1.30–2.59; P = 0.026) were considered at higher risk as predictors for T2DM.{Table 4}

 Discussion



The study reports strong positive correlation between uric acid and HbA1c levels. The current results are confirmative with other reported that correlations between uric acid levels and diabetes, family history of hypertension, metabolic syndrome, CHD, and diabetic nephropathy.[21],[22]

Further, we reported a correlation between uric acid levels and age, BMI (kg/m2), continuation of DM, and WC. These reported results are in agreement with the literature.[8] The correlation between uric acid and HbA1c levels can be considered as an important risk factor. While preceding researches reported thaturic acid was associated with T2DM, and similarly, we established positive association between these variables.[3],[8-11],[15],[21],[22]

We also report a positive correlation between a high level of uric acid and DBP–SBP among patients with T2DM. Uric acid levels were correlated with the risk of metabolic syndrome and BP and TSH. The association of uric acid levels and T2DM incidence has been indicated in several other populations,[13],[23],[24] which are consistent with our studies among patients with T2DM.

Furthermore, other scientists[13],[21],[22] reported strong positive relationships between the uric acid level, thyroid diseases, and vitamin D deficiency in patients with T2DM. Finally, the prevention and early detection of elevated level of uric acid in both patients with T2DM and hypertension can provide effective investigative tool in reducing CVD. The result with relation to incident prediabetes is consistent with previous research on this subject using impaired fasting glucose level as an end point. This could indicate that serum uric acid is more closely associated with early-phase rather than late-phase mechanisms that play a role in the development of T2DM.[13],[22]

Serum uric acid level has been investigated in relation to incident T2DM in individuals with impaired fasting glucose level by Kramer et al.,[21] who found a significant association after adjusting for various confounders in study population with characteristics similar to ours. It is possible that residual confounding in the previous study could account for this difference. These covariates were particularly impactful in our multivariable-adjusted model.[13],[21],[22]

The strengths of our study include its prospective cohort nature, which minimizes the chance of reverse causation, its long follow-up time, and our ability to adjust for a large set of confounders. However, the study has several limitations to discuss. All data were collected using a standardized protocol with rigorous quality control. First, oral glucose tolerance tests were not performed, so we could not identify participants with impaired glucose tolerance (IGT), another characteristic of prediabetes. It is possible that serum gamma-glutamyltransferase and uric acid may show different associations with IGT than that with impaired fasting glucose. Second, only one time point was recorded for the subjects in this study. Third, possible selection bias was observed as this is not a study of consecutive patients seen at our institution.

 Conclusion



The results suggest a strong positive correlation between serum uric acid level with levels of SBP and DBP, age, BMI, duration of DM, and WC among patients with T2DM. This study ascertains that an increase in uric acid level may be due to elevated level of HbA1c, metabolic syndrome, diabetes, obesity, and/or hypertension.

Acknowledgement

This work was generously supported and funded by the Qatar Diabetes Association, Qatar Foundation, Doha, Qatar. We would like to thank the Istanbul Medipol University for their support and ethical approval (Research Protocol and IRB no. 10840098-604.01.01-E.8421 and Research Protocol and IRB no. 10840098-604.01.01-E.3193).

Financial support and sponsorship

The authors declared that this study has received no financial support.

Conflicts of interest

There are no conflicts of interest.

References

1Bener A, Keskin FE, Kurtuluş EM, Guzel M, Çekirdekçi EI, Kadıoğlu P, et al. Essential parameters and risk factors of the patients for diabetes care and treatment diabetes and metabolic syndrome. Diabetes Metab Syndr 2017;11:S315-20.
2Bener A, Al-Hamaq AO, Kurtuluş EM, Abdullatef WK, Zirie M. The role of vitamin D, obesity and physical exercise in regulation of glycemia in type 2 diabetes mellitus patients. Diabetes Metab Syndr 2016;10:198-204.
3Bandaru P, Shankar A. Association between serum uric acid levels and diabetes mellitus. Int J Endocrinol 2011;2011:604715.
4Zoppini G, Targher G, Negri C, Stoico V, Perrone F, Muggeo M, et al. Elevated serum uric acid concentrations independently predict cardiovascular mortality in type 2 diabetic patients. Diabetes Care 2009;32:1716-20.
5Ciarla S, Struglia M, Giorgini P, Striuli R, Necozione S, Properzi G, et al. Serum uric acid levels and metabolic syndrome. Arch Physiol Biochem 2014;120:119-22.
6Clausen JO, Borch-Johnsen K, Ibsen H, Pedersen O. Analysis of the relationship between fasting serum uric acid and the insulin sensitivity index in a population-based sample of 380 young healthy Caucasians. Eur J Endocrinol 1998;138:63-9.
7Wun YT, Chan CS, Lui CS. Hyperuricaemia in type 2 diabetes mellitus. Diabetes Nutr Metab 1999;12:286-91.
8Fouad M, Fathy H, Zidan A. Serum uric acid and its association with hypertension, early nephropathy and chronic kidney disease in type 2 diabetic patients. J Bras Nefrol 2016;38:403-10.
9Niskanen L, Laaksonen DE, Lindström J, Eriksson JG, Keinänen-Kiukaanniemi S, Ilanne-Parikka P, et al. Serum uric acid as a harbinger of metabolic outcome in subjects with impaired glucose tolerance: the Finnish Diabetes Prevention Study. Diabetes Care 2006;29:709-11.
10Nakanishi N, Okamoto M, Yoshida H, Matsuo Y, Suzuki K, Tatara K. Serum uric acid and risk for development of hypertension and impaired fasting glucose or type II diabetes in Japanese male office workers. Eur J Epidemiol 2003;18:523-30.
11Zoppini G, Targher G, Bonora E. The role of serum uric acid in cardiovascular disease in type 2 diabetic and non-diabetic subjects: a narrative review. J Endocrinol Invest 2011;34:881-6.
12Modan M, Halkin H, Karasik A, Lusky A. Elevated serum uric acid—a facet of hyperinsulinaemia. Diabetologia 1987;30:713-8.
13Bener A, Ozdenkaya Y, Al-Hamaq AOAA, Barisik CC, Ozturk M. Low vitamin D deficiency associated with thyroid disease among type 2 diabetic mellitus patients. J Clin Med Res 2018;10:707-14.
14Dehghan A, van Hoek M, Sijbrands EJ, Hofman A, Witteman JC. High serum uric acid as a novel risk factor for type 2 diabetes. Diabetes Care 2008;31:361-2.
15Kodama S, Saito K, Yachi Y, Asumi M, Sugawara A, Totsuka K, et al. Association between serum uric acid and development of type 2 diabetes. Diabetes Care 2009;32:1737-42.
16Oda E, Kawai R, Sukumaran V, Watanabe K. Uric acid is positively associated with metabolic syndrome but negatively associated with diabetes in Japanese man. Intern Med 2009;48:1785-91.
17Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811-21.
18Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al.; International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640-5.
19International Diabetes Federation (IDF). IDF Diabetes Atlas. 8th ed. Brussels: International Diabetes Federation; 2017. http://www.diabetesatlas.org/resources/2017-atlas.html
20American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes-2018. Diabetes Care 2018;41:S13-27.
21Kramer CK, Von Mühlen D, Jassal SK, Barrett Connor E. Serum uric acid levels improve prediction of incident type 2 diabetes in individuals with impaired fasting glucose: the Rancho Bernardo Study. Diabetes Care 2009;32:1272-3.
22van der Schaft N, Brahimaj A, Wen KX, Franco OH, Dehghan A. The association between serum uric acid and the incidence of prediabetes and type 2 diabetes mellitus: the Rotterdam Study. PLoS One 2017;12:e0179482.
23Rafieian-Kopaei M, Behradmanesh S, Kheiri S, Nasri H. Association of serum uric acid with level of blood pressure in type 2 diabetic patients. Iran J Kidney Dis 2014;8: 152-4.
24Forman JP, Choi H, Curhan GC. Uric acid and insulin sensitivity and risk of incident hypertension. Arch Intern Med 2009;169:155-62.