Prevalence of diabetic complications is frequently increasing in world wide. There are many factors which are involved to cause complications in type 2 diabetes mellitus. Hyperuricemia is considered to be one of the risk factors to cause type 2 diabetes mellitus and also cardiovascular disease. Moreover, uric acid is commonly associated with glucose intolerance, hypertension, dyslipidaemia and metabolic syndrome. Since 1950s uric acid was recognized as factor to contribute in the pathogenesis of cardiovascular diseases such as stroke and ischemic heart disease [6]. Extensive epidemiological and experimental evidence suggests that uric acid is a relevant and independent risk factor for cardiovascular disease and renal disease, mostly in patients with hypertension, heart failure or diabetes [7].
The present study was recognized that type 2 diabetic subjects have pathological changes, which was stated by the investigation of parameters related to dyslipidaemia (increased Tgl & LDL levels), oxidative stress (increased MDA and decreased FRAP) and endothelial dysfunction (reduced NO availability). Since uric acid is an independent risk factor to cause type 2 diabetes and cardiovascular disease, our study focused to elucidate the correlation of uric acid with other risk factors include triglyceride, MDA, FRAP, NO and homocysteine are as follows.
Correlated of Uric acid with Triglyceride
Graph 3 shows slight uphill linear pattern, but few values are scattered in a wide band showing linear relationship between uric acid and triglyceride, statistically insignificant. As we know dyslipidaemia and uric acid are individual risk factors to cause complications in diabetes. But uric acid is strongly correlated with triglyceride than MDA and NO. An earlier cross-sectional study has found that uric acid levels are associated with HDL-c and triglycerides than insulin resistance in dyslipidaemia subjects. Where, atherogenic index of plasma was found to be significantly correlated with uric acid [8]. Moreover, Post-hoc analysis of GREACE and the life trials changed interest to focus on serum uric acid level and its contribution in atherosclerotic cardiovascular disease [9]. Sharma S et al has identified dyslipidaemia in type 2 diabetic subjects with reduced level of uric acid. It shows strong benefit effect of uric acid in diabetes [10]. But still it is uncertain that whether uric acid has strong beneficial or harmful effect associated with other parameters.
Correlation of Uric acid with Malondialdehyde (MDA)
The major function of uric acid is either an antioxidant or pro-oxidant depends on variety of factors. UA is a powerful signalling molecule that can affect intracellular signal transduction leads to generation of oxidants through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and expression of pro-inflammatory mediators [11]. Additionally, increased UA level through impaired renal excretion was observed in subjects with obese, insulin resistant and hypertension. Where in local ischemia condition uric acid production increases parallel to reactive oxygen species (ROS). However, clinical and experimental evidence suggest that uric acid has antioxidant property. This antioxidant activity of uric acid is overcome by pro-oxidant and pro-inflammatory effects of ROS [1,9]. In our study Graph 4 shows slight downhill, values of upper linear line scattered in a wide band represents negative relationship of uric acid with MDA (p=0.056), but statistically insignificant. This clarifies that uric acid has modest pro-oxidant property to cause oxidative stress in type 2 diabetic subjects. Anyhow a greater number of clinical studies are required to establish and confirm the pro-oxidant activity of uric acid.
Correlation of Uric acid with FRAP
Uric acid is a powerful scavenger of free radicals and provides 60% of free -radical scavenging capacity in plasma [12].The present study Graph 5 displays slight uphill linear pattern and few values are scattered in a wide distribution, positive relationship was found between uric acid and FRAP and statistically significant. An earlier study was observed higher level of FRAP in subjects with hyperuricemia and also found decreased uric acid level with reduced antioxidant capacity [12]. Glantzounis G.K observed lowering uric acid by allopurinol has protective effect in situation associated with oxidative stress (e.g. ischaemia reperfusion injury, cardiovascular disease) [1]. Nieto F.J et al evaluated that higher level of uric acid was associated with elevated antioxidant capacity among individuals with atherosclerosis [13].
Uric acid is a unique scavenger of peroxynitrite in the extracellular space. However, uric acid cannot scavenge superoxide, and presence of ascorbic acid thiols are required for complete scavenging of peroxynitrite [2]. Uric acid not only acts as scavenger, but also stabilizes ascorbate in biological fluids. Ascorbate stabilization is particularly evident in human and largely due to iron chelation by uric acid. Depletion of serum uric acid causes rapid oxidation of ascorbic acid where largely depends on iron [14]. Additionally, our study also supporting that uric acid has antioxidant property, since we observed significant Correlation uric acid with FRAP (‘p’=<0.05). This indicates that uric acid has high possibility of antioxidant property rather than pro-oxidant.
Correlation of uric acid with NO
In diabetes, hyperglycaemia may contribute to endothelial dysfunction in several ways. Reduced level of NO in diabetes maybe due to limited availability of NADPH (Nicotinamide adenine dinucleotide phosphate), a necessary cofactor for eNOS, may occur as a result of decreased activity of pentose phosphate pathway leads to decrease NO production. Oxidative stress promotes generation of superoxide (O2-), an anion generated by a number of pathways which can quench NO, reducing its bioavailability despite normal production leads to endothelial dysfunction [15]. Uric acid also plays a major role to decreases the bioavailability of NO in bovine aortic endothelial cells and adipocytes [2].
Still the mechanism of uric acid to damage organs is incompletely understood, but there is increasing evidence that endothelial dysfunction is a fundamental mechanism where uric acid may affect the cardiovascular and renal function. Graph 6 demonstrates slight uphill linear pattern where uric acid values are scattered in a wide band, showing positive relationship but statistically insignificant. Earlier studies have been observed that allopurinol lowers uric acid by inhibiting xanthine oxidase and improves endothelial function by interacting with anion superoxide production [7]. The experimental data directly implicate uric acid in endothelial dysfunction, but few other study reports in humans made controversial [16]. In our study uric acid was not correlated with endothelial dysfunction, the reason might be due to sample size.
Correlation of Uric acid with Homocysteine
Both uric acid and homocysteine are well known risk factors for cardiovascular disease [17]. Hyperhomocysteinemia is one of the important factors for cardiovascular disease. Graph 7 illustrates moderate uphill linear pattern where few uric acid values are scattered in a wide band, showing positive relationship but not significant as FRAP. However, relationship of uric acid with homocysteine is better than MDA, NO and triglyceride. An earlier study has observed that elevated level of homocysteine in male gout patients and hyperhomocysteinemia was not correlated with uric acid, but it was inversely correlated with renal dysfunction [18].Where homocysteine triggers free radical production and impairs endothelial function and initiates cardiovascular risk [19]. Our study was identified endothelial dysfunction, but it was not correlated with uric acid and homocysteine.
The present study was evaluated the correlation of uric acid with other risk factor to predict complications in type 2 diabetes mellitus. Uric acid is an individual risk factor to cause cardiovascular disease; it may be more predictable marker if correlates with other risk factors. Our study was found significant correlation of uric acid with total antioxidant capacity (FRAP) and moderate significant correlation with triglyceride and homocysteine. But statistically insignificant correlation of uric acid was found with total cholesterol, LDL, HDL, MDA and NO. The present study supports earlier reports that uric acid has strong predictive antioxidant property rather than pro-oxidant. Increasing uric acid may help to reduce oxidants and future complications in type 2 diabetes. However, we require large scale randomized study to get accurate report on antioxidant activity of uric acid because our study also found moderate significant correlation of uric acid with triglycerides and homocysteine.