The thoughtful discussion by Wang et al.  of their finding that serum urate concentration ‘predicts subclinical atherosclerosis independently of BMI’ emphasizes an unresolved question – Is hyperuricaemia a mechanism promoting atherogenesis, or simply a marker of other metabolic abnormalities that are the culprits? Although we tend to favour the second alternative, we also believe that it is difficult to come to a clear-cut answer concerning this quandary based solely on associations of serum uric acid levels with atherosclerosis. Moreover, there are data not discussed by Wang et al. that we believe are relevant to this issue.
Insulin-mediated glucose uptake varies widely in nondiabetic individuals, and the more insulin resistant, the greater the degree of compensatory hyperinsulinaemia [2-4]. Although hyperinsulinaemia in insulin-resistant individuals can prevent frank decompensation of glucose homeostasis, it can also have untoward effects of tissues that have retained normal insulin sensitivity; a prime example of this is the kidney [4-6]. For example , in a study of presumably healthy individuals, without diabetes or gout, the degree of insulin resistance was directly related (P < 0.001) to both the insulin response to oral glucose (r = 0.81) and the serum uric acid concentration (r = 0.69) and inversely related to uric acid clearance (r = −0.49, P < 0.002). The plasma insulin response was also inversely related to uric acid clearance (r = −0.33, P < 0.05) and directly related to serum uric acid concentration (r = 0.61, P < 0.001). Finally, the greater the decrease in uric acid clearance, the higher the serum uric acid concentration (r = −0.61, P < 0.001). These findings are consistent with the notion that the more resistant to insulin-mediated glucose disposal, the greater will be the serum uric acid concentration in presumably healthy individuals, secondary to an insulin-induced decrease in renal uric acid clearance.
Subsequent to this initial publication , several reports were published supporting the proposed link between insulin resistance/compensatory hyperinsulinaemia, decreased renal uric acid clearance and elevated serum uric acid concentration. For example, evidence was published confirming in apparently healthy individuals the presence of a direct, highly significant relationship between resistance to insulin-mediated glucose disposal and serum uric acid concentration . The next step in the proposed relationship between insulin resistance/compensatory hyperinsulinaemia, decreased uric acid clearance and elevated uric acid concentrations is that increases in plasma insulin concentration will decrease renal uric acid excretion. Evidence for this proposed mechanism is available, and insulin infusions have been shown to decrease renal uric acid clearance in both healthy volunteers  and patients with essential hypertension . Of particular interest was the finding in patients with essential hypertension that ‘higher uric acid levels and lower renal urate clearance rates cluster with insulin resistance and dyslipidaemia’. Coming at this cluster of related metabolic abnormalities from another direction, apparently healthy persons with asymptomatic hyperuricaemia are hyperinsulinaemic, with higher systolic and diastolic blood pressures, and dyslipidaemic (high triglyceride and low high-density lipoprotein concentrations) as compared to normouricaemic subjects .
Returning to the observations of Wang and associates , it seems reasonable to suggest that the increased urate concentrations that predicted enhanced atherogenesis in their population were secondary to insulin resistance/compensatory hyperinsulinaemia, and a consequent decrease in renal uric acid excretion. Furthermore, it also seems reasonable to suggest that increased uric acid concentration in apparently healthy individuals is another of the multiple metabolic abnormalities that comprise the insulin resistance syndrome [3, 11, 12]. Given current knowledge, it is relatively simple to follow the iconic advice of Claude Rains in the movie Casablanca ‘to round up the usual suspects’. On the other hand, it has been difficult deciding the degree to which any of the cardiometabolic risk factors associated with insulin resistance/hyperinsulinaemia that make up the insulin resistance syndrome contribute to the accelerated atherogenesis.
On the other hand, uses of modern genetic methods, such as Mendelian randomization, are providing greater insight into disease pathogenesis in a way that has not previously been possible short of randomized clinical trials. In particular, this approach has been extremely useful in discerning causal links between biomarkers and disease. The principle underlying these analyses is that if a biomarker (such as serum uric acid levels) is causally related to the pathogenesis of disease (coronary heart disease), then genetic variation resulting in changes in the biomarker should effect disease risk in the same way predicted by the biomarker levels [13, 14]. Mendelian randomization uses genotypes which are robustly associated with the risk factor of interest as instrumental variables. Because these genotypes are randomly assigned when passed from parents to children, this approach accounts for reverse causation and confounding, which can plague epidemiologic studies.
Perhaps the most well-known example of the utility of this approach was the analysis of Voight et al. questioning the causal link between high-density lipoprotein cholesterol concentrations and myocardial infarction . Recent data using this approach also question a causal role for elevated uric acid concentrations in the development of ischaemic heart disease. Thus, Palmer et al. found no evidence that uric acid levels were casually linked with ischaemic heart disease or blood pressure. Of note, they did find evidence for a causal association between body mass index and uric acid levels . An analogous approach has been taken with serum uric acid levels and type 2 diabetes . Whilst this study did demonstrate a significant association between serum uric acid levels and type 2 diabetes, it also failed to demonstrate a causal link between the two.
Taken together, these studies provide support for the idea that it is not the serum uric acid levels per se that are increasing heart disease risk, but rather that this is another biomarker of the underlying physiological condition (insulin resistance) that is the culprit. These analyses are also important because they strongly suggest that pharmacological treatments specifically targeted at lowering serum uric acid levels would not be expected to have an impact on the development of either type 2 diabetes or cardiovascular disease.