D-FENFLURAMINE IMPROVES HEPATIC INSULIN ACTION IN STREPTOZOTOCIN-DIABETIC RATS

We have examined the effect of chronic (21 days) oral administation of the serotoninergic anorectic drug d-fenfluramine (5 mg/kg) in a rat m odel of non-insulin-dependent diabetes (without obesity), as induced b y injection of a low dose (45 mg/kg) of streptozotocin at 6 weeks, and characterized by marked hyperglycaemia and hepatic and peripheral ins ulin resistance. The following parameters were assessed: (1) basal blo od glucose and insulin levels, and (2) basal and insulin-stimulated in vivo glucose production and glucose utilization, using the insulin-cl amp technique in conjunction with isotopic measurement of glucose turn over. In the d-fenfluramine-treated diabetic rats, postabsorptive basa l 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 plasm a 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-f ed untreated diabetic rats. The impaired suppression of hepatic glucos e output by insulin, caused by diabetes, was totally reversed by d-fen fluramine, while pair-feeding did not modify hepatic insulin resistanc e. 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 benefi cial effect on peripheral glucose utilization in the rats receiving d- fenfluramine is mainly due to chronic food restriction (as a consequen ce of the anorectic properties of the drug). By contrast, d-fenflurami ne counteracts liver insulin resistance in the present rat model of di abetes by a mechanism not related to its anorectic properties.