Troglitazone decreases serum uric acid concentrations in Type II diabetic patients and non-diabetics
Dear Sir, Hyperuricaemia is commonly seen in association with obesity, impaired glucose tolerance, hypertension and dyslipidaemia [1, 2], which are the central characteristics of the insulin resistance syndrome. The association between isolated hyperuricaemia and insulin resistance is, however, still not defined [3]. To assess whether or not hyperuricaemia is an expression of insulin resistance, it seems reasonable to measure alterations in serum uric acid concentrations during treatment with an insulin sensitising agent in patients with Type II (non-insulin-dependent) diabetes mellitus. With this aim, we recruited 95 (61 men) Type II diabetic patients who were given 200 mg of troglitazone twice a day and met the following criteria: no use of drugs that affect uric acid metabolism, no increase in serum creatinine concentration ( < 115 mmol/l) and availability of paired determinations of serum uric acid concentrations before and after troglitazone treatment. Their age (mean ± SD) was 61.1 ± 10.3 years and BMI was 25.4 ± 3.0. All medications other than troglitazone (if any) were unchanged throughout the study period of 9.7 ± 7.6 months. All available data from 6 months before troglitazone and all data after it were combined respectively and used for statistical analysis by Student's paired t-test. Serum uric acid concentrations decreased significantly after treatment with troglitazone from a mean baseline value of 327 ± 71 mmol/l to 298 ± 71 mmol/l (p < 0.0001): 351 ± 71 to 321 ± 65 in men, 286 ± 54 to 244 ± 48 in women (both p < 0.0001) (Fig. 1). This decrease occurred concomitantly with those in HbA1c values (8.4 ± 1.3 to 7.8 ± 1.3 %, p < 0.0001) and triglyceride concentrations (2.2 ± 1.3 to 1.9 ± 1.2 mmol/l, p < 0.01) and in a subset of patients (n = 34) in parallel with fasting plasma glucose (10.5 ± 2.1 to 8.3 ± 2.4 mmol/l, p < 0.0001) and insulin concentrations (52.2 ± 22.2 to 34.8 ± 15.0 pmol/l, p < 0.0001) and therefore also HOMA-IR, a simple measure of insulin resistance obtained by fasting plasma concentration of glucose (mmol/l) ́ insulin (mU/ml)/22.5 (4.3 ± 2.4 to 2.2 ± 1.2, p < 0.0001). Furthermore, in six non-diabetic subjects (two healthy volunteers and four hyperuricaemic patients) who consented to participate in a troglitazone trial (200 mg/day for 4 weeks), serum uric acid decreased similarly (375 ± 60 to 298 ± 30 mmol/l, p < 0.02). A 24-h urinary excretion of uric acid (3.8 ± 1.1 to 3.3 ± 0.8 mmol/day), uric acid clearance (9.0 ± 4.0 to 8.3 ± 3.3 ml/min), and the ratio of uric acid clearance to that of creatinine (10.0 ± 4.3 to 11.0 ± 5.0 %) determined in 12 Type II diabetic patients did not differ significantly between pre-treatment and post-treatment. It is therefore difficult to explain the decrease in serum uric acid concentrations given previous reports that hyperinsulinaemia reduces renal clearance of uric acid through coupling with increased sodium reabsorption at proximal tubules [4±7]. Haemodilution seems unlikely, because haematocrit values did not alter greatly with the treatment (data not shown). In addition, improvement of glycaemic control is not the cause because urinary excretion of uric acid is facilitated by hyperglycaemia itself and vice versa. Although the mechanism is not clear, we speculate that troglitazone could have some effect on uric acid production because increased purine biosynthesis and turnover with its attendant increase in serum uric acid concentrations due to increased activity of the hexose monophosphate shunt can be conceptually linked to insulin resistance or hyperinsulinaemia or both. Our results vary from another study [8] which showed no statistically significant alteration in serum uric acid concentrations or serum triglyceride, total-cholesterol and HDL-cholesterol, plasminogen activator inhibitor-1, conventional variables of insulin resistance, after troglitazone treatment (200 mg/day) in 25 Type II diabetic patients for 8 weeks using a randomised double-blind procedure. The reason for this disparity is not clear but is presumably due to differences in the dosage used in both studies: theirs was half of ours. It is not clear from this in vivo study whether the hypouricaemic effect of troglitazone is a direct pharmacological action or an indirect one secondary to reduction of insulin resistance. We favour the latter, however, because biochemical variables for insulin resistance changed concomitantly with serum uric acid concentrations in our study but the lack of changes in these variables was not accompanied by alterations in serum uric acid concentrations in the other study [8]. Such an effect has not been reported in the other thiazolidinediones, pioglitazone and rosiglitazone. We showed an antihyperuricaemic effect of troglitazone through a mechanism distinct from increased renal clearDiabetologia (2000) 43: 814±820