Uric acid, metabolic syndrome, T2DM, and atheroscleropathy

The importance of hyperuricemia and the clustering phenomenon of the metabolic syndrome were first described by Kylin in 1923 when he described the clustering of three clinical syndromes: hypertension, hyperglycemia, and hyperuricemia [16]. In 1988, Reaven GM described the important central role of insulin resistance in the seminal Banting lecture where he described Syndrome X, which has now become known as the metabolic syndrome (MS) and/or the insulin resistance syndrome (IRS) [17]. Seven decades after the clustering phenomenon was reported by Kylin (1993), Reaven GM and Zavaroni I et al. suggested that hyperuricemia be added to the cluster of metabolic and hemodynamic abnormalities associated with insulin resistance and/or hyperinsulinemia of Syndrome X [18].

The four major players in the MS are hyperinsulinemia, hypertension, hyperlipidemia, and hyperglycemia. Each member of this deadly quartet has been demonstrated to be an independent risk factor for CHD and capable of working together in a synergistic manner to accelerate both non-diabetic atherosclerosis and the atheroscleropathy associated with MS, PD, and T2DM.

In a like manner, hyperuricemia, hyperhomocysteinemia, ROS, and highly sensitive C- reactive protein (hsCRP) each play an important role in expanding the original Syndrome X described by Reaven in the atherosclerotic process. The above quartet does not stand alone but interacts in a synergistic manner resulting in the progression of accelerated atherosclerosis and arterial vessel wall remodeling along with the original players and the A-FLIGHT-U toxicities (table 1). The MS of clinical clustering has been renamed multiple times over the past 16 years indicating its central importance to cardiovascular disease and was included in the recent National Cholesterol Educational Program – Adult Treatment Panel III (NCEP ATP III) clinical guidelines in order to assist the clinician in using this important tool to evaluate additional cardiovascular risk [16-19].


Hyperinsulinemia and Hyperamylinemia

Insulin, proinsulin, and amylin individually and synergistically activate the renin – angiotensin system (RAS) with subsequent increase in Ang II. Ang II is the most potent endogenous inducer of NAD(P)H oxidase, increasing NAD(P)H, which increases vascular – intimal reactive oxygen species (ROS) and superoxide (O2-•) [19,20]. There are many deleterious effects of hyperinsulinemia in addition to its being responsible for sodium, potassium, water, and urate retention in proximal kidney (table 3) [21].


Hypertension is strongly associated with hyperuricemia. SUA levels are elevated in hypertension and are present in 25% of untreated hypertensive subjects, 50% of subjects taking diuretics, and greater than 75% of patients with malignant hypertension [22]. Potential mechanisms involved with the association of hyperuricemia and hypertension include the following: 1. Decreased renal blood flow (decreased GFR) stimulating urate reabsorption, 2. Microvascular (capillary) disease resulting in local tissue ischemia. 3. Ischemia with associated increased lactate production that blocks urate secretion in the proximal tubule and increased uric acid synthesis due to increased RNA-DNA breakdown and increased purine (adenine and guanine) metabolism, which increases uric acid and ROS through the effect of xanthine oxidase (XO). 4. Ischemia induces increased XO production and increased SUA and ROS. These associations with ischemia and XO induction may help to understand why hyperuricemia is associated with preeclampsia and congestive heart failure.

Because endothelial dysfunction, local oxidant generation, elevated circulating cytokines, and a proinflammatory state are common in patients with cardiovascular disease and hypertension there is an increased level of oxidative – redox stress within vascular tissues. Oxidative – redox stress results in impaired endothelium-dependent vasodilation with quenching of endothelial nitric oxide (eNO) and allows the endothelium to become a net producer of ROS specifically superoxide as the endothelial nitric oxide synthase (eNOS) enzyme uncouples to produce superoxide instead of eNO. This similar mechanism applies equally well to that associated with type 2 diabetes and congestive heart failure [11,19]. It is important to note that allopurinol and oxypurinol (XO inhibitors) are capable of reversing the impaired eNO production in both heart failure [23-25] and type 2 diabetes mellitus (T2DM) [26].

Lin KC et al. were able to demonstrate that blood pressure levels were predictive for cardiovascular disease incidence synergistically with serum uric acid level [27]. Two separate laboratories have demonstrated the development of systemic hypertension in a rat model of hyperuricemia developed with a uricase inhibitor (oxonic acid) after several weeks of treatment [28,29]. This hypertension was associated with increased renin and a decrease in neuronal nitric oxide synthase in the juxtaglomerular apparatus. Prevention of this hypertension was accomplished by an ACE inhibitor and to a lesser extent L-arginine. These findings indicate an interacting role of the renin- angiotensin system and the NOS enzyme. Hypertension, neural nitric oxide synthase (nNOS) and renin changes were also prevented by maintaining uric acid levels in the normal range with allopurinol or benziodarone (a uricosuric).

These above models have provided the first challenging evidence that uric acid may have a pathogenic role in the development of hypertension, vascular disease, and renal disease [11].