Amelioration of Some Manifestations of Metabolic Syndrome in Rats by Allopurinol Irrespective of Lowering Serum Uric Acid Level: Role of Adiponectin

Some studies suggest that increased serum uric acid may simply be a consequence of oxidative stress or hyperinsulinemia present in subjects with metabolic syndrome, while others postulate that uric acid could have a contributory causal role. Although lowering uric acid in fructose fed rats can improve insulin sensitivity and features of metabolic syndrome, the mechanisms involved in these beneficial effects remain unclear. The strong association between serum uric acid and the metabolic syndrome led some authors to postulate a correlation between uric acid level and adipose tissue. Down regulation of adiponectin, an adipokine released from adipose tissue, is associated with obesity-linked diseases including coronary artery disease and type 2 diabetes. Clinical observations demonstrated that hypoadiponectinemia is closely related to endothelial dysfunction in blood vessels. The aim of the present work was to investigate whether the beneficial effects of allopurinol in metabolic syndrome are secondary to reduction of serum uric acid or to other mechanisms such as elevation of adiponectin level. Materials and Methods: A model of metabolic syndrome in male Wistar rats was induced by feeding animals high fat diet and single intraperitoneal injection of low dose streptozotocin. 3 weeks later, rats that developed metabolic syndrome received a vehicle or glibenclamide 0.5 mg/kg/day (as a standard therapy of type 2 diabetes mellitus). Allopurinol was administered in combination with glibenclamide in two different doses, 50 mg/Kg and 100 mg/Kg/day. Treatment was continued for 3 weeks. Metabolic syndrome parameters, adiponectin level, vascular reactivity in addition to intima/media ratio of aorta and liver histopathology were investigated. Results: Allopurinol induced dose dependent improvement in insulin sensitivity and serum glucose but uric acid reduction was dose independent. Allopurinol showed dose dependent improvement in endothelial function, intima/media ratio of aorta with remarkable improvement in features of hepatic steatosis. Both low and high dose of allopurinol induced elevation of adiponectin compared to untreated group with no significant difference between both doses. Conclusion: Allopurinol could improve some parameters of metabolic syndrome in a rat model of metabolic syndrome irrespective to lowering uric acid level. The effects of allopurinol may be related to elevation of the lowered level of adiponectin associated with obesity linked diseases