Diabetes mellitus risk is increased by prolonged usage of antidepressants (ADs). Although various mechanisms are suggested for their diabetogenic potential, whether a direct effect of ADs on pancreatic β-cells is involved is unclear. We examined this idea for three ADs:paroxetine, clomipramine and, with particular emphasis, fluoxetine, on insulin secretion, mitochondrial function, cellular bioenergetics, K ATP channel activity and caspase activity in murine and human cell-line models of pancreatic β-cells. Metabolic assays showed that these ADs decreased the redox, oxidative respiration and energetic potential of β-cells in a time and concentration dependent manner at concentrations (100 nM) well within their plasma therapeutic window. These effects were related to inhibition of mitochondrial complex I and III activity.Consistent with impaired mitochondrial function, lactate output was increased and insulin secretion decreased. Neither fluoxetine, antimycin nor rotenone could reactivate K ATP channel activity blocked by glucose unlike the mitochondrial uncoupler, FCCP. Chronic, but not acute, AD increased oxidative stress and activated caspases, 3, 8 and 9. To conclude, paroxetine, clomipramine and fluoxetine were all found to be cytotoxic at therapeutic concentrations on pancreatic beta-cells; an action suggested to arise by inhibition of mitochondrial bioenergetics, oxidative stress and induction of apoptosis. These actions may help explain the diabetogenic potential of these ADs in humans.

The oxidative metabolism of energy substrates has a paramount role in the stimulus secretion pathway of insulin. However, the role of glycolytic pathway in pancreatic beta cells is not very well understood. To address this, we have investigated and compared the functional effects of two mitochondrial substrates (glucose and α-ketoisocaproate) between the human (1.1B4) and murine (MIN6) pancreatic beta cell lines. MTS assay was conducted as an indicator of the metabolic activity of both cell lines. Polarographic detection of (ΔO2) and lactate were used to measure the oxygen consumption rate and anaerobic glycolysis respectively. The mitochondrial redox state was monitored via RH123 distribution and NAD(P)H autofluorescence. The metabolic assays showed glucose stimulated MTS reduction in MIN6 cells in a time and concentration dependent manner and nor in 1.1B4. Both sub strates failed to affect OCR, NADPH and increased lactate production in 1.1B4 cells. However, they stimulated OCR, increased NADPH, increased lactate output but was less extent and hyperpolarized the mitochondria in MIN6 cells. The above results showed that 1.1B4 cells are mainly depending on the glycolytic pathway different from MIN6 cells which rely on mitochondrial respiration. In conclusion, 1.1B4 cell line represents a new model to study the bioenergetics profile because it depends on the anaerobic glycolysis rather than aerobic respiration of the other models such as MIN6 and islets.

Fluoxetine, a widely used antidepressant that primarily acts as a selective serotonin reuptake inhibitor, inhibits various membrane receptors and Ca 2+ influx by unknown mechanism. In addition, it has been shown that Ca2+ is control mitochondrial metabolism and respiration. Here, effect of fluoxetine on the voltage gated Calcium channels in MIN6 cells was examined. Using Ca 2+ imaging is to assess intracellular calcium. Fluoxetine 30 µM inhibited ca 2+ levels. These results indicated a tighter binding of fluoxetine to the Calcium than to the resting state of other channels, suggesting a more potent inhibition of Ca 2+ channels at physiological resting membrane potential. Altogether, these data demonstrate that clinically relevant concentrations of fluoxetine exert a voltage-dependent block of channels that may contribute to this antidepressant’s pharmacological effects.

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