We have examined the effect of chronic (20 days) oral administration of benfluorex (35 mg/kg) in a rat model of non-insulin-dependent diabetes mellitus (NIDDM), as induced by injection of streptozotocin 5 days after birth and characterized by frank hyperglycaemia, hypoinsulinaemia, and hepatic and peripheral insulin resistance. In the benfluorex-treated diabetic rats, basal plasma glucose levels were decreased (7.9 +/- 0.2 mM as compared with 17.2 +/- 1.1 mM in the pair-fed untreated diabetic and 6.7 +/- 0.2 mM in the benfluorex-treated non-diabetic rats) while the basal and the glucose-stimulated (IVGTT) plasma insulin levels were not improved. The lack of improvement of glucose-induced insulin release after benfluorex treatment was confirmed under in vitro conditions (perfused pancreas). In the benfluorex-treated diabetic rats, basal glucose production and overall glucose utilization were normalized. Following hyperinsulinaemia (euglycaemic clamp), glucose production was normally suppressed while overall glucose utilization was not significantly improved. Since benfluorex exerts a predominant action on the liver in the present rat model of diabetes, and since increased basal hepatic glucose output is a major metabolic abnormality and is responsible for much of the elevated fasting blood glucose levels in NIDDM, the use of such a compound in NIDDM may be potentially relevant.