D-Fenfluramine improves hepatic insulin action in streptozotocin-diabetic rats

Abstract

We have examined the effect of chronic (21 days) oral administration of the serotoninergic anorectic drug d-fenfluramine (5 mg/kg) in a rat model of non-insulin-dependent diabetes (without obesity), as induced by injection of a low dose (45 mg/kg) of streptozotocin at 6 weeks, and characterized by marked hyperglycaemia and hepatic and peripheral insulin resistance. The following parameters were assessed: (1) basal blood glucose and insulin levels, and (2) basal and insulin-stimulated in vivo glucose production and glucose utilization, using the insulin-clamp technique in conjunction with isotopic measurement of glucose turnover. In the d-fenfluramine-treated diabetic rats, postabsorptive basal plasma glucose levels were decreased (7.8 ± 0.3 mM as compared to 14.9 ± 0.1 mM in the untreated diabetic rats) while the basal plasma insulin levels were unchanged. A similar reduction of the basal plasma glucose levels was observed in the pair-fed untreated diabetic group (8.3 ± 0.2 mM). Basal glucose turnover was reduced by 45% ( P < 0.01) in the d-fenfluramine-treated diabetic rats as well as in the pair-fed untreated diabetic rats. The impaired suppression of hepatic glucose output by insulin, caused by diabetes, was totally reversed by d-fenfluramine, while pair-feeding did not modify hepatic insulin resistance. The whole body insulin-mediated glucose uptake in the diabetic rats was also significantly improved by d-fenfluramine treatment. Such an effect was also found in the pair-fed untreated group. Thus the beneficial effect on peripheral glucose utilization in the rats receiving d-fenfluramine is mainly due to chronic food restriction (as a consequence of the anorectic properties of the drug). By contrast, d-fenfluramine counteracts liver insulin resistance in the present rat model of diabetes by a mechanism not related to its anorectic properties.