|Year : 2015 | Volume
| Issue : 3 | Page : 141-147
Are uric acid values surrogate for insulin resistance in apparently healthy subjects across a spectrum of body mass index?
A Puneeth, Poornima A Manjrekar, Anupama Hegde, MS Rukmini, Madan Gopal Rajan, Mamatha T Shenoy
Department of Biochemistry, Centre for Basic Sciences, Kasturba Medical College, Manipal University, Mangalore, Karnataka, India
|Date of Web Publication||16-Jul-2015|
Poornima A Manjrekar
Department of Biochemistry, Centre for Basic Sciences, Kasturba Medical College, Manipal University, Mangalore - 575 004, Karnataka
Source of Support: None, Conflict of Interest: None
Background: The concept of insulin resistance initially proposed in diabetic patients requiring high doses of insulin is now known to be associated with major public health problems, including obesity, hypertension, coronary artery disease, and metabolic syndrome. Serum uric acid (SUA) values are also elevated in the above conditions and proposed to reflect the insulin-resistant state. Objective: To determine whether SUA levels can be used as a surrogate for insulin resistance calculated as homeostatic model assessment insulin resistance (HOMA-IR) in apparently healthy, normal weight, overweight, and obese population. Materials and Methods: A cross-sectional study done in 150 subjects of both genders aged 20-40 years was divided equally based on their body mass index into three groups namely normal weight, overweight, and obese as per National Institutes of Health classification. Fasting plasma glucose, fasting serum insulin, and SUA were estimated. HOMA-IR was calculated. Results: Mean waist circumference, waist-hip ratio, fasting insulin, fasting glucose, uric acid, and HOMA-IR were found to be elevated in both overweight and obese groups. Mean uric acid levels were 4.9 mg/dL, 5.4 mg/dL, and 6.3 mg/dL and mean HOMA-IR values are 2.2, 3.3, and 7.3, respectively, in normal weight, overweight, and obese subjects. Significant correlation of uric acid with insulin resistance calculated as HOMA-IR was not found in any of the three groups. Conclusion: There was an incremental increase in fasting glucose, fasting insulin, uric acid, and HOMA-IR from normal weight to overweight to obese subjects in a systematic proportion. Significant correlation of uric acid with fasting insulin and insulin resistance was not seen and hence cannot be used as the surrogate marker for insulin resistance in the apparently healthy population.
Keywords: Insulin resistance, obesity, uric acid
|How to cite this article:|
Puneeth A, Manjrekar PA, Hegde A, Rukmini M S, Rajan MG, Shenoy MT. Are uric acid values surrogate for insulin resistance in apparently healthy subjects across a spectrum of body mass index?. Int J Health Allied Sci 2015;4:141-7
|How to cite this URL:|
Puneeth A, Manjrekar PA, Hegde A, Rukmini M S, Rajan MG, Shenoy MT. Are uric acid values surrogate for insulin resistance in apparently healthy subjects across a spectrum of body mass index?. Int J Health Allied Sci [serial online] 2015 [cited 2019 Sep 20];4:141-7. Available from: http://www.ijhas.in/text.asp?2015/4/3/141/160869
| Introduction|| |
Obesity is one of the most important, widespread, still neglected health issue of the public, associated with significant increase in both morbidity and mortality and is an imminent overwhelming problem seen in both well and less developed countries.  In India, obesity is emerging as an important health problem particularly in urban areas, paradoxically co-existing with malnutrition. Almost 30-65% of adults in urban India are either overweight or obese or have abdominal obesity. , Insulin resistance, a condition where insulin-induced glucose uptake is impaired in the peripheral tissues is a result of inhibition of the insulin signaling pathway leading to hyperinsulinemia in an effort to control blood glucose. The concept of insulin resistance initially proposed in the diabetic patients is now known to be associated with major public health issues including obesity, hypertension, coronary artery disease, and metabolic syndrome. Increased waist circumference (WC), waist-hip ratio (WHR), hyperinsulinemia, and hyperuricemia are well-known features of obesity. , Uric acid, the primary end product of purine metabolism in humans, is found to be elevated in a variety of disorders such as hypertension, type 2 diabetes, and metabolic syndrome. Raised levels of serum uric acid (SUA) have been proposed to be an expression of the insulin-resistant state. Although detailed mechanism of insulin resistance due to hyperuricemia is not known, multiple factors including inhibition of nitric oxide synthase, , higher levels of extracellular adenosine, and elevated synthesis of fatty acid-acyl-CoA in peripheral tissues, which results in elevated levels of AMP and hence implicated in hyperuricemia. ,, As uric acid is an indirect marker, it will be difficult to establish an independent association between uric acid and insulin resistance. Previous studies show the relationship of insulin resistance and uric acid in various degrees of obesity  or association of obesity with increasing quartiles of uric acid  but very few studies exist to relate uric acid and insulin resistance with normal weight and overweight. With this proposed association of uric acid and insulin resistance, this study was taken up to find out if uric acid can be used as a surrogate for insulin resistance in apparently healthy population across a spectrum of body mass index (BMI).
| Materials and methods|| |
The study was designed as a cross-sectional study in 150 subjects of both genders aged 20-40 years among South Indian local population in the city of Mangalore, Karnataka matched for age and gender, divided equally into three groups as per National Institutes of Health (NIH)  namely normal weight, overweight, and obese and later into BMI classification proposed for South Asian population ,, into three groups namely normal weight, overweight, and obese. Selection of patients was done through a questionnaire, which included the type of diet and history of smoking and alcohol consumption, and the subjects who did not fit the selection criteria were excluded from the study. Written informed consent was obtained from each subject at the time of selection. The ethical clearance was obtained from Institutional Ethics Committee. Exclusion criteria for all subjects in the three groups include individuals with history of diabetes mellitus, hypertension, nephropathy, endocrine disorders or carcinoma of any etiology, gouty arthritis, Polycystic ovarian disease, women on estrogen supplements including oral contraceptives and on hormone replacement therapy, and individuals who were on nonsteroidal anti-inflammatory drugs in the previous 2 weeks. Individuals with incidental finding of fasting blood sugar ≥ 126 mg/dL were also excluded from the study.
Anthropometric measurements such as height, weight, WC, and hip circumference (HC) were collected, and BMI and WHR were calculated. Overnight fasting serum samples were collected for biochemical parameters. Fasting plasma glucose (FPG) was estimated by glucose oxidase and uric acid by uricase - POD kits supplied by Aspen diagnostics (India). For fasting plasma insulin, the samples were stored at –20°C until analysis, was measured by Sandwich ELISA using kits supplied by DRG International, Inc., (Germany). Insulin resistance as homeostatic model assessment (HOMA-IR) index was calculated as (fasting insulin [μIU/dl] × fasting serum glucose [mg/dl]/405). 
Statistical analysis was carried out using SPSS statistical software (Version 17.5). Results are presented as mean and standard deviation for group characteristics; ANOVA was applied for group comparison, Tukey's test for multiple comparisons, and Pearson's correlation to determine the linear correlation between the variables. P < 0.05 was considered statistically significant.
| Results|| |
Of the 150 subjects involved in the study 72 were females and the mean age of the subjects was 31.5 (6.1) years.
[Table 1] shows the general characteristics of the study population after being divided into three groups. There is no significant difference in the mean age between the three groups. The anthropometric parameters such as weight, BMI, WC, HC, and WHR showed a significant difference between the groups. In case of biochemical parameters, mean values of FPG, fasting insulin, uric acid, and HOMA-IR were the highest in obese subjects and the lowest in normal weight subjects with significant difference between obese and other two groups but between normal weight and overweight, the difference did not reached statistical significance.
|Table 1: General characteristics of the study population divided based on NIH classification|
Click here to view
[Table 2] shows the general characteristics as per division for proposed South Asian cut-off for BMI. Only obese group showed a significant difference in both anthropometric parameters and biochemical parameters compared to other two groups. No difference was found between normal weight and overweight except for BMI and HC.
When the Pearson's correlation was applied for anthropometric measures versus biochemical parameters in all the three groups as per NIH classification [Table 3], only BMI had good correlation with HOMA-IR in all three groups in spite of incremental increase in mean concentration of all biochemical parameters across all three groups. Within the biochemical parameters [Table 4] FPG correlated with fasting insulin levels only with normal weight and overweight subjects. Insulin and HOMA-IR have shown a strong correlation (P < 0.001) in all three groups whereas there was no correlation seen between plasma insulin and HOMA-IR with uric acid levels.
|Table 3: Correlation between anthropometry and biochemical measurements (NIH classification)|
Click here to view
Correlating the anthropometric measurements with biochemical parameters when the groups were divided as per proposed South Asian classification [Table 5], the significant correlation for BMI, WC, and WHR was observed with all biochemical parameters. Between the biochemical parameters [Table 6] FPG and HOMA-IR correlated with fasting insulin levels in all three groups. Uric acid and HOMA-IR correlated with fasting glucose only in the obese population.
|Table 5: Correlation between anthropometry and biochemical measurements for South Asian division|
Click here to view
|Table 6: Correlation of biochemical parameters for South Asian BMI division|
Click here to view
| Discussion|| |
This study was performed in a nondiabetic population-based cohort taking into account the different grades of obesity to study the relation of uric acid with insulin resistance. There are many serum markers that have been found to rise with obesity and insulin resistance. One such marker is uric acid, which has also been implicated as a marker for cardiovascular diseases and nephrolithiasis.
Elevation in the serum level of uric acid across the three groups was seen in this study with elevation in body weight and BMI with percentage rise in SUA levels of 12.5% in overweight and 31.25% increase in obese group reflecting the findings of Ferrara et al.  Lee et al. and Yoo et al.  found an increase in BMI with increasing quartiles of uric acid in their respective studies.
Percentage rise in HOMA-IR value of 48.7% in overweight and 234.9% in obese which shows that insulin resistance increases linearly with an increase in BMI replicating the findings of Tumova et al. and McAuley et al. 
HOMA-IR correlated with BMI in all three groups [Table 3]. There was no correlation with uric acid and FPG and insulin [Table 4]. Fabbrini et al. in their study suggest that the oxidative stress of which uric acid is a marker is not a major cause of insulin resistance in obesity. Significant correlation was found only between fasting insulin and HOMA-IR in our study, which is along the lines of many of the older studies. ,
There are increasing data that suggest the proposed cut-offs for defining overweight and obesity, are not appropriate for Asian Indians, and that Asian Indians are at a risk of developing obesity related comorbidities at lower levels of BMI and WC. Vasudevan et al. in their study found higher WC and increased risk of metabolic syndrome when South Asians were classified according to the proposed classification.  Similar findings were also found in studies by Singh et al. and Snehalatha et al.
After dividing the study population on lines of proposed BMI classification for Asian population, uric acid was found to be raised in obese compared to nonobese with the percentage rise in the mean uric acid of 15.6%. Similar rise was seen with HOMA-IR with percentage rise of 178% from nonobese to the obese group. Significant correlation for uric acid in the proposed Asian classification was found with WC and WHR but not with insulin or HOMA-IR, by which it can be implicated that rise in uric acid levels are probably the earliest signs of obesity even before the onset of insulin resistance as elevation in the WC is an early sign of obesity. These results are similar to the findings by Lin et al. and Chen et al. who found a significant correlation of uric acid with BMI and WC. Elevated levels of uric acid in obese people in comparison with nonobese individuals, seems to be an early metabolic alteration that accompanies other features of insulin resistance syndrome, which can be explained with the presence of elevated intracellular adenosine derived from higher AMP concentrations due to increased synthesis of fatty acid-acyl-CoA in peripheral tissues. It has also been observed in early obesity elevated levels of uric acid which are derived from elevated plasma fatty acids. 
Alternative proposed mechanism suggests the effect of uric acid on endothelial dysfunction and overproduction of reactive oxygen species, and uric acid induced a reduction in production of nitric oxide in adipose tissue. Oxidative stress in adipocytes has also been proposed as an important initiator of insulin resistance, leading to the metabolic dysregulations observed in insulin resistance syndrome. 
Other important finding in this study was an incremental increase in the mean values of fasting glucose, fasting insulin, uric acid, and HOMA-IR from normal weight to overweight to obese subjects in a systematic proportion which was also seen with the anthropometric measurements such as weight, BMI, WC, HC, and WHR. The rise in the mean levels of glucose, insulin, and HOMA-IR was also reflected in the studies by Cruz-Dominguez et al. This shows that elevation in biochemical parameters is associated with the rise in body weight and increased abdominal adiposity.
It is uncertain whether elevated uric acid levels are the result or the cause of insulin resistance. Many studies have implicated the cause of hyperuricemia as secondary to insulin resistance. Rise in AMP levels, a precursor for uric acid formation is said to raise uric acid levels. ,, Other studies suggest hyperinsulinemia and insulin resistance secondary to hyperuricemia subsequent to the provocation of inflammatory and oxidative processes in adipocytes leading to insulin resistance. , Hence, whether hyperuricemia precedes hyperinsulinemia and insulin resistance or the vice versa is still controversial. The results of our study are in support of the former.
| Conclusion|| |
In this study, where uric acid was accessed as a surrogate for insulin resistance by comparing and correlating it with HOMA-IR and fasting insulin levels in apparently healthy volunteers across a spectrum of BMI, it was found that SUA did not correlate with the marker of insulin resistance. However, uric acid levels showed a steady increase in the groups with a 12.5% rise from normal weight to overweight and a 16.7% rise from overweight to obese. However, uric acid correlated well with WC and WHR, which are also proposed as anthropometric markers of metabolic syndrome. Hence, although values of uric acid did not reflect that of HOMA-IR, evidence was found for increasing levels of uric acid with rise in obesity and may be used as the surrogate marker for insulin resistance in apparently healthy overweight and obese population when divided according to both NIH classification and proposed BMI classification for South Asian population. A more homogenous population would have been more suited for the study and needs to be validated in a study design specifically for the Asian classification and appropriate sample size.
To determine whether SUA can be used as a surrogate for insulin resistance, ideally the study should have included diabetic and hypertensive subjects too, to complete the spectrum from normal to diseased. This study concentrated only on apparently healthy normal, overweight, and obese individuals. High SUA levels are associated with purine-rich diet (nonvegetarian food). In this study, subjects consuming both vegetarian and mixed diet were included but were not further classified based on their diet. More appropriate sample size was also required to validate the findings when divided according to proposed classification for the Asian population.
Future scope based on this study can include a more homogenous population comprising of subjects with diabetes and hypertension, with appropriate sample size. Furthermore, the effect of these parameters, when the study population would be divided based on quartiles of uric acid, may also be taken up.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Landsberg L, Aronne L, Beilin L, Burke V, Igel L, Lloyd-Jones D, et al
. Obesity-related hypertension: Pathogenesis, cardiovascular risk, and treatment. Obesity 2013;21:8-24.
Kalra S, Unnikrishnan AG. Obesity in India : The weight of the nation. J Med Nutr Nutraceuticals 2012;1:37-41.
Niranjan G, Anitha D, Srinivasan AR, Velu VK, Venkatesh C, Babu MS, et al.
Association of inflammatory sialoproteins, lipid peroxides and serum magnesium levels with cardiometabolic risk factors in obese children of South Indian population. Int J Biomed Sci 2014;10:118-23.
Lann D, LeRoith D. Insulin resistance as the underlying cause for the metabolic syndrome. Med Clin North Am 2007;91:1063-77, viii.
Odegaard JI, Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science 2013;339:172-7.
Jin M, Yang F, Yang I, Yin Y, Luo JJ, Wang H, et al.
Uric acid, hyperuricemia and vascular diseases. Front Biosci (Landmark Ed) 2012;17:656-69.
Sachs L, Batra K, Zimmermann B. Medical implications of hyperuricemia. Med Health 2009;92:353-5.
Bakker SJ, Gans RO, ter Maaten JC, Teerlink T, Westerhoff HV, Heine RJ. The potential role of adenosine in the pathophysiology of the insulin resistance syndrome. Atherosclerosis 2001;155:283-90.
Gil-Campos M, Aguilera CM, Cañete R, Gil A. Uric acid is associated with features of insulin resistance syndrome in obese children at prepubertal stage. Nutr Hosp 2009;24:607-13.
Pasalic D, Marinkovic N, Feher-Turkovic L. Uric acid as one of the important factors in multifactorial disorders - Facts and controversies. Biochem Med (Zagreb) 2012;22:63-75.
Ferrara LA, Wang H, Umans JG, Franceschini N, Jolly S, Lee ET, et al.
Serum uric acid does not predict incident metabolic syndrome in a population with high prevalence of obesity. Nutr Metab Cardiovasc Dis 2014;24:1360-4.
Lee JM, Kim HC, Cho HM, Oh SM, Choi DP, Suh I. Association between serum uric acid level and metabolic syndrome. J Prev Med Public Health 2012;45:181-7.
WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004;363:157-63.
Vasudevan D, Stotts AL, Mandayam S, Omegie LA. Comparison of BMI and anthropometric measures among South Asian Indians using standard and modified criteria. Public Health Nutr 2011;14:809-16.
Singh LC, Sikri SL, LCMG. Body mass index and obesity: Tailoring "cut-off" for an Asian Indian male population. Med J Armed Forces India 2008;64:350-3.
Muniyappa R, Lee S, Chen H, Quon MJ. Current approaches for assessing insulin sensitivity and resistance in vivo
: Advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab 2008;294:E15-26.
Yoo TW, Sung KC, Shin HS, Kim BJ, Kim BS, Kang JH, et al.
Relationship between serum uric acid concentration and insulin resistance and metabolic syndrome. Circ J 2005;69:928-33.
Tumova E, Sun W, Jones PH, Vrablik M, Ballantyne CM, Hoogeveen RC. The impact of rapid weight loss on oxidative stress markers and the expression of the metabolic syndrome in obese individuals. J Obes 2013;2013:1-10.
McAuley KA, Williams SM, Mann JI, Walker RJ, Lewis-Barned NJ, Temple LA, et al.
Diagnosing insulin resistance in the general population. Diabetes Care 2001;24:460-4.
Fabbrini E, Serafini M, Colic Baric I, Hazen SL, Klein S. Effect of plasma uric acid on antioxidant capacity, oxidative stress, and insulin sensitivity in obese subjects. Diabetes 2014;63:976-81.
Jones CN, Abbasi F, Carantoni M, Polonsky KS, Reaven GM. Roles of insulin resistance and obesity in regulation of plasma insulin concentrations. Am J Physiol Endocrinol Metab 2000;278:E501-8.
Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G. Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). J Clin Invest 1997;100:1166-73.
Snehalatha C, Viswanathan V, Ramachandran A. Cutoff values for normal anthropometric variables in asian Indian adults. Diabetes Care 2003;26:1380-4.
Lin SD, Tsai DH, Hsu SR. Association between serum uric acid level and components of the metabolic syndrome. J Chin Med Assoc 2006;69:512-6.
Chen LY, Zhu WH, Chen ZW, Dai HL, Ren JJ, Chen JH, et al.
Relationship between hyperuricemia and metabolic syndrome. J Zhejiang Univ Sci B 2007;8:593-8.
Soltani Z, Rasheed K, Kapusta DR, Reisin E. Potential role of uric acid in metabolic syndrome, hypertension, kidney injury, and cardiovascular diseases: Is it time for reappraisal? Curr Hypertens Rep 2013;15:175-81.
Cruz-Domínguez MP, Cortés DH, Zarate A, Tapia-González Mde L, Alvarez-Acosta S, Damasio L, et al
. Relationship of ghrelin, acid uric and proinflammatory adipocytokines in different degrees of obesity or diabetes. Int J Clin Exp Med 2014;7:1435-41.
Nakamura K, Sakurai M, Miura K, Morikawa Y, Nagasawa SY, Ishizaki M, et al.
HOMA-IR and the risk of hyperuricemia: A prospective study in non-diabetic Japanese men. Diabetes Res Clin Pract 2014;106:154-60.
Baldwin W, McRae S, Marek G, Wymer D, Pannu V, Baylis C, et al.
Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes 2011;60:1258-69.
Krishnan E, Pandya BJ, Chung L, Hariri A, Dabbous O. Hyperuricemia in young adults and risk of insulin resistance, prediabetes, and diabetes: A 15-year follow-up study. Am J Epidemiol 2012;176:108-16.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]