Fluoxetine improves insulin sensitivity in obese patients with non-insulin-dependent diabetes mellitus independently of weight loss P Maheux, F Ducros, J Bourque, J Garon and J-L Chiasson Research Group on Diabetes and Metabolic Regulation, Clinical Research Institute of Montreal, Department of Medicine, Faculty of Medicine, University of Montreal OBJECTIVE: To study the effect of fluoxetine, a specific serotonin reuptake inhibitor, on insulin sensitivity in obese patients with non-insulin-dependent diabetes mellitus (NIDDM) independently of its action on body weight. RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled trial, insulin-mediated glucose disposal was measured in 12 obese patients with NIDDM on diet alone before and after four weeks of treatment with either placebo (n  6) or fluoxetine (n  6) at a dose level of 60 mg once a day. Insulin-mediated glucose disposal was assessed by the 2-step euglycemic hyperinsulinemic clamp technique. Patients were instructed on a weight- maintaining diet. RESULTS: Insulin infusion at 40 mU ? m 72 ? min 71 resulted in insulin levels of 720670 pmol ? L 71 with a mean plasma glucose value of 6.460.2 mmol ? L 71 . Compared to placebo, fluoxetine increased glucose disposal (M) by 2.4-fold (P < 0.05), the insulin sensitivity index (M/I) by 2.7-fold (P < 0.03) and the glucose metabolic clearance rate (MCR) by 2.9-fold (P < 0.03). Insulin infusion at 400 mU ? m 72 ? min 71 elicited insulin levels of 12 94761 512 pmol ? L 71 with a mean plasma glucose value of 5.660.4 mmol ? L 71 . Compared to placebo, fluoxetine increased M by 30% (P  NS), M/I by 40% (P < 0.04) and MCR by 23% (P < 0.04). Patient weight remained stable throughout the study with no change in dietary intake. CONCLUSION: Fluoxetine improves insulin-mediated glucose disposal in obese patients with NIDDM independently of weight loss. Keywords: fluoxetine; insulin resistance; obesity Introduction Insulin resistance is one of the major abnormalities in the development of non-insulin-dependent diabetes mellitus (NIDDM) 1 Therefore, in the treatment of type II diabetes, the rationale is to use new drugs which improve insuline sensitivity. We have already shown that fenfluramine, a serotonin agonist, improves plasma glucose in obese NIDDM patients without any change in plasma insulin or body weight. 2 More recently, it has been demonstrated that fenflur- amine exerts a direct effect on insulin sensitivity in obese NIDDM subjects. 3 Fluoxetine, another serotonin agonist, is currently used in the treatment of depression. 4 Its administration results in a centrally-mediated and highly selective inhibition of pre-synaptic 5-hydroxytryptamine re- uptake. 5 While this medication is currently adminis- tered as an antidepressant, it has been shown to possess anorectic properties and can induce significant weight reduction. 6,7 We, as others, have previously demonstrated that in obese patients with NIDDM, fluoxetine is efficient in producing weight loss and decreasing plasma glucose as well as insulin concen- trations and glycosylated hemoglobin. 8–11 It is not clear, however, whether these effects are due to a direct action of the drug or are secondary to weight loss. Like fenfluramine, 2,3,12,13 fluoxetine may impact on insulin-mediated glucose disposal independently of its effect on body weight. To answer this question, we examined, in a double-blind, placebo-controlled trial, the influence of fluoxetine on insulin sensitivity in obese weight-stable patients with NIDDM. Research design and methods Patient selection Twelve obese volunteers with NIDDM were recruited for the study. NIDDM was defined according to National Diabetes Data Group criteria, 14 and only patients treated with diet alone were included. Obesity was characterized by a body mass index over 27 kg  m 72 . All subjects were weight stable, in good general health and free of major vascular complica- tions. None was taking medications known to affect Correspondence: J-L Chiasson, Research Center, Hoˆ tel-Dieu de Montre´ al, 3850 St. Urbain Street, Montre´ al (Que´ bec) H2W 1T8, Canada. Received 15 November 1995; revised 24 April 1996; accepted 25 September 1996 International Journal of Obesity (1997) 21, 97–102 ß 1997 Stockton Press All rights reserved 0307–0565/97 $12.00