Preserved response to diuretics in rosiglitazone-treated subjects with insulin resistance: a randomized double-blind placebo-controlled crossover study

Thiazolidinediones (TZDs) are associated with fluid retention that has been suggested to be resistant to treatment with loop diuretics. This resistance is thought to be caused by upregulation of renal epithelial sodium channels (ENaCs). In this study, we tested whether these mechanisms are of clinical significance. We conducted a well-controlled study in 12 insulin-resistant nondiabetic participants, who received treatment for 9 weeks with either rosiglitazone at a dosage of 4 mg b.i.d. or placebo. The aim of the study was to investigate whether upregulation of ENaCs by rosiglitazone reduces furosemide's natriuretic response and enhances the response to the ENaC inhibitor amiloride. The natriuretic response to furosemide and amiloride and the amount of α-ENaC in urinary exosomes were quantified. Rosiglitazone neither reduced furosemide-induced natriuresis nor changed furosemide's concentration-effect curve. Furthermore, rosiglitazone did not change either amiloride-induced natriuresis nor the amount of urinary α-ENaC. This study challenges previous findings regarding TZD-related ENaC upregulation and suggests that TZD-induced fluid retention should respond normally to loop diuretics.