Dapagliflozin and xanthine oxidase inhibitors improve insulin resistance and modulate renal glucose and urate transport in metabolic syndrome.

Abstract

Disturbance in glucose and uric acid metabolism is the major disorder of metabolic syndrome (MetS). The kidneys play an important role in the management of glucose and uric acid. The aim of our study was to investigate alterations in renal glucose and uric acid transporters in animals with MetS after treatment with dapagliflozin and xanthine oxidase inhibitors (allopurinol and febuxostat). Sprague-Dawley rats were fed normal chow or a high fructose diet for the first 3months. The fructose-fed animals were then treated with dapagliflozin, allopurinol, febuxostat, or no treatment for the next 3months. Fasting glucose, insulin resistance, and hyperuricaemia were improved in all treatment groups except that in the fructose group (all p<0.05). Both allopurinol and febuxostat reversed the increase in levels of sodium glucose cotransporter (SGLT) 1, SGLT2, and glucose transporter (GLUT) 2 (all p<0.05). Dapagliflozin alleviated hyperuricaemia and induced uricosuria without affecting serum xanthine oxidase activity. Dapagliflozin suppressed the expression of GLUT9, urate transporter, and urate anion exchanger 1 (all p<0.05), which was similar to the effects of allopurinol and febuxostat. The results suggest that treatment with dapagliflozin and xanthine oxidase inhibitors improved insulin resistance and reversed the increased expression of glucose and urate transporters in the kidney.