Elevated serum uric acid levels in metabolic syndrome: an active component or an innocent bystander?
Introduction
The metabolic syndrome (MetS) is a modern “epidemic” leading to increased risk of cardiovascular disease (CVD) and diabetes mellitus (DM) [1], [2], [3], [4]. The principal underlying pathophysiologic abnormality is insulin resistance (IR), which is mainly associated with abdominal obesity. Insulin resistance eventually results in dyslipidemia, hypertension, impaired carbohydrate metabolism, and other metabolic abnormalities [5]. At least 5 organizations have recommended clinical criteria for the diagnosis of MetS [6], [7], [8], [9], [10], [11], [12]. These criteria are similar in many aspects, but they also have differences concerning the predominant causes of MetS and the definition of obesity.
Serum uric acid (SUA) levels are often increased in subjects with MetS [13], [14]. However, none of the proposed sets of diagnostic criteria include SUA levels in the definition of MetS. In 2001, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) published the most widely used set of diagnostic criteria [6]. These criteria include elevated plasma triglyceride (TRG) levels (≥150 mg/dL [1.69 mmol/L]), decreased levels of high-density lipoprotein cholesterol (HDL-C) (<40 mg/dL [1.04 mmol/L] in men and <50 mg/dL [1.29 mmol/L] in women), elevated blood pressure (BP) (≥130/85 mm Hg), increased fasting plasma glucose levels (≥ 110 mg/dL [6.1 mmol/L]), and abdominal obesity (waist circumference >102 cm in men and >88 cm in women). Recently, the International Diabetes Federation (IDF) proposed a new MetS definition [10]. The IDF definition suggested that abdominal obesity (plus other 2 criteria) is required for the diagnosis of MetS. Furthermore, IDF lowered waist circumference values defining abdominal obesity (≥94 cm in Europid men and ≥80 cm in Europid women) and fasting plasma glucose levels defining impaired fasting glucose (≥100 mg/dL [5.54 mmol/L]). However, it is believed that the NCEP ATP III criteria are currently the most useful for the diagnosis of MetS, as IDF definition seems to unacceptably increase the incidence of MetS in the general population [15]. Moreover, a recent American Heart Association/National Heart, Lung, and Blood Institute statement maintains the NCEP ATP III criteria except for defining glucose levels as ≥100 mg/dL (5.54 mmol/L) [12]. It also adopts the IDF-proposed criteria for the definition of abdominal obesity in certain ethnic groups (eg, Asians).
Large epidemiologic studies underlined the association of hyperuricemia with the components of MetS, suggesting that SUA levels could be included in the definition of MetS [13], [16], [17], [18], [19], [20], [21]. Moreover, as the number of MetS variables increased, so did the SUA concentration [14]. Serum uric acid levels may also be a reliable predictor of the “pre-MetS” in obese youths [22].
Therefore, we undertook this review of current literature on the relationship between uric acid (UA) and IR/MetS aiming to answer the question of whether elevated SUA levels are an active component or just an associative link to the MetS. In addition, we briefly review the effect of drugs used in the treatment of MetS on SUA levels.
Section snippets
Direct association of SUA levels with MetS and IR
Large epidemiologic studies demonstrated that the prevalence of MetS showed a graded increase according to SUA levels [14], [17], [18], [23], [24]. Moreover, SUA concentration was positively correlated with BP, waist-to-hip ratio, homeostasis model assessment index (an index of IR), body mass index, and levels of fasting plasma glucose, insulin, TRG, high-sensitivity C-reactive protein, and inversely correlated with HDL-C levels [14], [17], [18], [20], [21], [23], [24], [25], [26]. Insulin
Indirect association of SUA levels with MetS and IR
Hypertension, commonly encountered in MetS, could mediate an indirect relationship between MetS and SUA levels. Indeed, hypertension could lead to hyperuricemia by several mechanisms [72].
Hypertension leads to vascular disease and increased renal vascular resistance [73], both resulting in decreased renal blood flow, which in turn stimulates urate reabsorption [73]. Moreover, microvascular disease leads to local ischemia and release of lactate, which compete with urate transporter in the
Uric acid and CVD risk
Many studies have underlined the positive association between SUA and CVD risk. Indeed, SUA concentration was shown to be an independent risk factor for CVD [114], [115], [116], [117], [118]. In the Augsburg cohort of the MONICA (World Health Organization Monitoring Trends and Determinants in Cardiovascular Diseases) study (including 1044 men) [119], increased SUA levels independently from other known risk factors predicted all-cause (HR, 2.8; 95% CI, 1.6-5.0) and CVD mortality (HR, 2.2; 95%
The effect of drugs used in the treatment of MetS on SUA levels
A selection of cardiovascular drugs that have a neutral or even lowering effect on SUA levels may be important in decreasing CVD risk in MetS. Several drugs can influence SUA concentration [63], [127] (Table 1). Firstly, diuretics, even in low doses, may increase SUA concentration by increasing the net reabsorption of UA in the nephron proximal tubule [128]. The diuretic-induced SUA elevation is evident within a few days after initiating treatment [129], [130]. β-Blockers (propranolol [131],
Conclusions and suggestions for future work
Raised SUA levels are associated with the MetS. Data presented herein clearly show that UA is not just an innocent bystander in MetS, but it is strongly interrelated with metabolic disarrangements of MetS. Specifically, IR leads to elevated SUA levels through both direct and indirect mechanisms, which include increased urate production as well as decreased renal urate excretion. Increased SUA levels may in turn worsen IR and associated features, such as hypertension, dyslipidemia, endothelial
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