Uric Acid, Type 2 Diabetes, and Cardiovascular Diseases: Fueling the Common Soil Hypothesis?

Uric acid is the final oxidation product of purine catabolism. Excess serum accumulation can lead to various diseases, and most notably uric acid is causally involved in the pathogenesis of gouty arthritis. Also, for more than 50 years, increased serum concentrations of uric acid have been implicated in cardiovascular disease. Uric acid’s contribution to atherosclerotic vascular disease, however, is still somewhat controversial. Various mechanisms have been suggested through which uric acid may be implicated in the atherosclerotic process and its clinical complications. Uric acid can act as a prooxidant, particularly at increased concentrations, and may thus be a marker of oxidative stress (1)(2), but it may also have a therapeutic role as an antioxidant (3)(4). Plasma uric acid concentrations correlate with longevity in primates and other mammals (5), a characteristic that is presumably a function of urate’s antioxidant properties. Thus, it is unclear whether increased concentrations of uric acid in diseases associated with oxidative stress, such as atherosclerotic coronary heart disease (CHD), stroke, and peripheral arterial occlusive disease, are a protective response or a primary cause. Some researchers have proposed that hyperuricemia-induced oxidative stress represents a cause of the metabolic syndrome (6). Hyperuricemia has been found to be associated with obesity and insulin resistance, and consequently with type 2 diabetes (7)(8). Further potentially important biological effects of uric acid relate to endothelial dysfunction by inducing antiproliferative effects on endothelium and impairing nitric oxide production and inflammation, e.g., through increased C-reactive protein expression, although these issues are considered controversial (9)(10). Finally, uric acid may play a role in immune activation with subsequent increased chemokine and cytokine expression (11)(12). Thus, although there are plausible mechanisms to suggest uric acid as a potential direct mediator of cardiometabolic and other chronic diseases (except for gout), this is still a controversial area. Metabolic syndrome, type 2 diabetes, and atherosclerotic vascular disease are characterized by various established but also emerging risk factors, and interestingly, these three disorders have several risk factors in common. This has led Stern in 1995 (13) to put forward his “common soil” hypothesis. As mentioned above, uric acid presents one of the candidates that may be involved in these three cardiometabolic disorders.