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Fluoxetine and clomipramine inhibit mitochondrial respiration in a murine pancreatic β-cell line In man, the use of antidepressants has been associated with both hyperglycaemia (Derijks et al. 2008) and an increased risk of type 2 diabetes (Brown et al. 2008). Since certain antidepressants target mitochondrial function (Souza et al 1994; Eto et al 1985) and as the latter is a key component of the glucose stimulated-insulin secretion pathway, the glycaemic affects of antidepressants may result from a direct action on beta-cell function. I have investigated this possibility by investigating the acute action of antidepressants on mitochondrial function within intact beta-cells. For this study, the MIN6 beta-cell model cell line was used. Polarographic detection of O2 consumption in cell suspensions was used to measure the rate of respiration (ΔO2) at 37°C. Fluorescence imaging of cells loaded with Rhodamine 123 was used to monitor mitochondrial membrane potential (Δψm) at 32°C. At 10 μM, the tricyclic antidepressant clomipramine inhibited glucose-stimulated ΔO2 by 12 ± 4 % (n = 20) whereas 100 μM of the drug inhibited ΔO2 by 27 ± 8 % (n = 18). Similar effects were seen with fluoxetine, a selective serotonin reuptake inhibitor; where at 10 μM, fluoxetine inhibited glucose-stimulated ΔO2 by 9.2 ± 2 % (n = 29) and at 100 μM it inhibited ΔO2 by 27 ± 5% (n = 17). These effects were all significantly different (p<0.05) to that of H20, the vehicle control (2.4±0.5%, n = 35; Kruskal-Wallis plus Conover-Inman post hoc test). The hyperpolarization in Δψm produced by 10 mM glucose was decreased by 0.2 ± 0.03 % min-1 (n = 3) with 10 μM fluoxetine and by 2 ± 1% min-1 (n = 3) with 100 μM fluoxetine, but was quenched with 100 μM clomipramine. In conclusion the antidepressants fluoxetine and clomipramine acutely inhibit mitochondrial function in pancreatic beta-cells; the expected corollary is that they will also inhibit insulin secretion.
Derijks et al. (2008) Eur. J. Clin. Pharm., 64, 531-538.
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