Objective To study the short-term effects of the serotoninergic anorectic drug d-fenfluramine on insulininduced glucose disposal.

Research Design and Methods A randomized double-blind placebocontrolled crossover trial with 1-wk treatment periods (2 × 15 mg/day d-fenfluramine) was conducted. Twenty obese subjects, 10 with normal oral glucose tolerance and 10 with non-insulin-dependent diabetes mellitus (NIDDM), were all treated with a weight-maintaining diet. Euglycemic-hyperinsulinemic glucose clamps with measurement of glucose kinetics with D-[3-³H]glucose were performed at either two (patients without NIDDM, 0.05 and 0.10 U · kg⁻¹ · h⁻¹) or three (patients with NIDDM, 0.05, 0.10, and 0.50 U · kg⁻¹ · h⁻¹) insulin delivery rates.

Results In the n·ndiabetic subjects, no significant changes in any metabolic or hormonal parameter were measured in the basal state or during the clamp despite a slight reduction in body weight (−1.2 ± 0.5 kg, P < 0.05). In the diabetic patients, no significant changes in body weight or basal plasma insulin levels were observed, but fasting blood glucose levels (8.0 ± 0.8 vs. 9.4 ± 1.1 mM, P < 0.005) and plasma free fatty acid concentrations (1150 ± 227 vs. 1640 ± 184 µM, P < 0.05) were significantly reduced after d-fenfluramine compared with placebo. During the clamp, insulin metabolic clearance rate (MCR) was similar after both placebo and d-fenfluramine; endogenous (hepatic) glucose production was similarly and almost completely suppressed, whereas glucose disposal was remarkably enhanced after cMenfluramine (average increase of glucose MCR 35 ± 12%, P < 0.02).

Conclusions Whatever the mechanism(s) involved, a 1-wk treatment with d-fenfluramine induces better blood glucose control and improves insulin sensitivity in obese patients with NIDDM independent of significant weight reduction; this last effect is not present in obese subjects with normal oral glucose tolerance.