These studies examined the effect of fenfluramine on insulin action and insulin secretion in healthy subjects and patients with non-insulin-dependent diabetes mellitus (NIDDM). In the first study, a double-blind crossover design was used in healthy subjects to compare the effect of short-term fenfluramine therapy (60 mg orally for 3 days) with placebo. Insulin secretion and whole-body insulin sensitivity (determined by frequently sampled intravenous glucose tolerance tests with analysis by the minimal-model method) were unchanged by fenfluramine. In the second study, involving patients with NIDDM inadequately controlled on submaximal to maximal doses of oral hypoglycemic agents, a double-blind crossover strategy was used to compare baseline studies (conducted after a run-in period) with fenfluramine (60 mg orally) or placebo for 4 wk. There was a signficant fall in fasting blood glucose after therapy with fenfluramine compared with the baseline study period (13.0 ± 1.2 vs. 8.4 ± 0.89 mM, mean ± SE, P < .01) with no significant fall in fasting serum insulin (20± 2 vs. 24 ± 3 (μU/ml) or C-peptide (1.3 ± 0.2 vs. 1.3 ± 0.1 nM). During euglycemichyperinsulinemic (1 mU · kg−1 · min−1) clamp studies there was a significant increase in insulin action from 12.7± 2.3 to 17.3 ± 1.8 min−1 103 μU · ml1 (P < .05), although clamp insulin levels were lower after fenfluramine treatment (136 ± 14 vs. 96 ± 9 μU/ml−1, P < .02), reflecting an enhanced metabolic clearance rate for insulin (12.7 ± 1.5 vs. 20.1 ± 2.1 ml · kg−1 · min−1P < .025). When insulin action was normalized for the prevailing insulin level during the clamp, the increase of insulin action/in concentration was more marked (0.11 ± 0.22 to 0.22 ±0.04 min−1 103μU · ml−1 <.005). The insulin secretory response to arginine was unchanged from 21 ± 4 to 22 ± 6 μU/ml at similar levels of glycemia. Chronic fenfluramine therapy can lower fasting plasma glucose and increase insulin sensitivity without affecting insulin secretion in patients with NIDDM. Acute fenfluramine treatment in healthy individuals has no effect on glucose metabolism. We conclude that in patients with inadequately controlled NIDDM, fenfluramine may serve as a useful adjunct to sulfonylurea therapy.

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