Adipose Tissue Insulin Resistance Is Positively Associated With Serum Uric Acid Levels and Hyperuricemia in Northern Chinese Adults

To evaluate whether the homeostasis model assessment (HOMA) is a reliable surrogate measure of in vivo insulin sensitivity in humans.

To explore the causal relationship between metabolic syndrome, type 2 diabetes and hyperuricemia. The prevalence of hyperuricemia in male adults with metabolic syndrome was increased and a large difference in prevalence of metabolic syndrome also existed in those with hyperuricemia compared with normouricemia. Even in those with normouricemia, higher serum uric acid levels were associated with metabolic syndrome. Serum uric acid was an independent risk factor for incident diabetes, and evidence showed that the patients with both gout and type 2 diabetes exhibited a mutual inter-dependent effect on higher incidences. Furthermore, obese patients often demonstrated insulin resistance and adipose tissue macrophage with low-grade inflammation, which is suggested to be the major contributor. Although alcohol intake is considered a risk for developing hyperuricemia, moderate alcohol intake showed a lower risk for developing type 2 diabetes and insulin resistance. Hyperinsulinemia reduces renal excretion of uric acid on the proximal tubular of the kidney leading to hyperuricemia, which has deleterious effects on endothelial function and on nitric oxide bioavailability, thus causing hyperinsulinemia. We found evidence to suggest that insulin resistance plays a potentially key role in the causal relationship between metabolic syndrome, type 2 diabetes and hyperuricemia. Furthermore, it is likely that hyperuricemia and insulin resistance share a bidirectional causal effect.

OBJECTIVE Hyperuricemia is strongly associated with obesity and metabolic syndrome and can predict visceral obesity and insulin resistance. Previously, we showed that soluble uric acid directly stimulated the redox-dependent proinflammatory signaling in adipocytes. In this study we demonstrate the role of hyperuricemia in the production of key adipokines. RESEARCH DESIGN AND METHODS We used mouse 3T3-L1 adipocytes, human primary adipocytes, and a mouse model of metabolic syndrome and hyperuricemia. RESULTS Uric acid induced in vitro an increase in the production (mRNA and secreted protein) of monocyte chemotactic protein-1 (MCP-1), an adipokine playing an essential role in inducing the proinflammatory state in adipocytes in obesity. In addition, uric acid caused a decrease in the production of adiponectin, an adipocyte-specific insulin sensitizer and anti-inflammatory agent. Uric acid–induced increase in MCP-1 production was blocked by scavenging superoxide or by inhibiting NADPH oxidase and by stimulating peroxisome-proliferator–activated receptor-γ with rosiglitazone. Downregulation of the adiponectin production was prevented by rosiglitazone but not by antioxidants. In obese mice with metabolic syndrome, we observed hyperuricemia. Lowering uric acid in these mice by inhibiting xanthine oxidoreductase with allopurinol could improve the proinflammatory endocrine imbalance in the adipose tissue by reducing production of MCP-1 and increasing production of adiponectin. In addition, lowering uric acid in obese mice decreased macrophage infiltration in the adipose tissue and reduced insulin resistance. CONCLUSIONS Hyperuricemia might be partially responsible for the proinflammatory endocrine imbalance in the adipose tissue, which is an underlying mechanism of the low-grade inflammation and insulin resistance in subjects with the metabolic syndrome.