Fluoxetine Impairs Insulin Secretion without Modifying Extracellular Serotonin Levels in MIN6 β-cells

Cataldo, Luis Rodrigo; Mizgier, María L.; Aranda, Eduardo; Mezzano, Diego; Olmos, Pablo; Galgani, José E.; Suazo, José; Santos, José Luis

doi:10.1055/s-0035-1549964

Cited by 15 publications

(24 citation statements)

References 30 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More recent studies confirm that 5‐HT is released along with insulin and ATP from β‐cells and/or released from a subset of islet cells and that secretion of 5‐HT is regulated by increased glucose concentrations in MIN6 β‐cells, as well as in human islets . However, a basal leakage or constitutive release of 5‐HT is most likely also present, as indicated by a high basal efflux of 5‐HT in mouse islet and MIN6 β‐cells loaded with 5‐HTP . Additionally, the turnover rate of 5‐HT in mouse islets and MIN6 β‐cells is estimated to be 2 hours, suggesting a rapid clearance of the amine.…”

Section: Introductionmentioning

confidence: 89%

Serotonergic regulation of insulin secretion

et al. 2018

View full text Add to dashboard Cite

The exact physiological role for the monoamine serotonin (5-HT) in modulation of insulin secretion is yet to be fully understood. Although the presence of this monoamine in islets of Langerhans is well established, it is only with recent advances that the complex signalling network in islets involving 5-HT is being unravelled. With more than fourteen different 5-HT receptors expressed in human islets and receptor-independent mechanisms in insulin-producing β-cells, our understanding of 5-HT's regulation of insulin secretion is increasing. It is now widely accepted that failure of the pancreatic β-cell to release sufficient amounts of insulin is the main cause of type 2 diabetes (T2D), an ongoing global epidemic. In this context, 5-HT signalling may be of importance. In fact, 5-HT may serve an essential role in regulating the release of insulin and glucagon, the two main hormones that control glucose and lipid homoeostasis. In this review, we will discuss past and current understanding of 5-HT's role in the endocrine pancreas.

show abstract

Section: Introductionmentioning

confidence: 89%

Serotonergic regulation of insulin secretion

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The MIN6 cell line is a well-established, time honored, model for the study of pancreatic β-cell function (Miyazaki et al, 1990;Ishihara et al, 1993;Daunt et al, 2006;Cataldo et al, 2015). The main advantage of a cell line for pancreatic β-cell research is that it large numbers of phenotypically homogenous cells are available which are devoid of paracrine and neuroendocrine effects that arise from interaction with the other endocrine and neuronal cell types that reside within the pancreatic islet (Ishihara et al, 1993).…”

Section: Cellsmentioning

confidence: 99%

“…Pancreatic β-cells secrete 5-HT which may exert autocrine effects (Bennet et al, 2015). However, an involvement of SERT for the cytotoxic effects of these ADs can be dismissed, since β-cells do not express the Slc64a gene that encodes for SERT nor do ADs affect the release of 5-HT from them (Cataldo et al, 2015) .…”

Section: The Effects Of the Ads Are Not Mediated By Blockade Of Serotmentioning

confidence: 99%

“…Similar trends are observed with clomipramine, a TCA, which also produces acute hyperglycaemia without hyperinsulinaemia in rodents (Sugimoto et al, 2003;Gomez et al, 2001) as well as in humans (Lustman et al, 1997;McIntyre et al, 2006). In murine models, intraperitoneal administration of fluoxetine or clomipramine produces maximal hyperglycaemia within the first 30-90 minutes of injection (Yamada et al, 1999;Sugimoto et al, 2003;Gomez et al, 2001); observations that also indicate a direct action of these drugs on the β-cell, an idea further supported by their ability to inhibit insulin secretion from isolated pancreatic β-cells (Antoine et al, 2004;Cataldo et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Editor’s Highlight: Therapeutic Concentrations of Antidepressants Inhibit Pancreatic Beta-Cell Function via Mitochondrial Complex Inhibition

Elmorsy

Al‐Ghafari

Helaly

et al. 2017

Toxicological Sciences

View full text Add to dashboard Cite

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.

show abstract

“…reported that chronic treatment of INS-1E β cells with fluoxetine (1 μM) impaired GSIS and increased the production of reactive oxygen species (ROS) resulting in damage to mitochondrial function 10 . Moreover, fluoxetine-induced impairment of GSIS observed in β cell lines may be independent of accumulation of extracellular 5-HT level 11 .…”

Section: Introductionmentioning

confidence: 97%

Selective serotonin reuptake inhibitor, fluoxetine, impairs E-cadherin-mediated cell adhesion and alters calcium homeostasis in pancreatic beta cells

Chang

Chen

Shen

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed drugs for mood disorders. Long term use of SSRIs is associated with an increased risk of diabetes, but the underlying mechanism(s) remains elusive. E-cadherin-mediated cell-cell adhesion and elevated [Ca2+]i are important for insulin release and pancreatic β cell functions. This study aims to investigate whether a SSRI, fluoxetine (Prozac), induces pancreatic β cell dysfunction through affecting E-cadherin and/or [Ca2+]i. Here we show that fluoxetine significantly reduces glucose stimulated insulin secretion (GSIS). MIN6 cells, an established murine immortalized β cell line, form smaller colonies of loosely packed cells with reduced cell-cell contact after fluoxetine treatment. Immunofluorescence staining reveals that fluoxetine increases cytoplasmic accumulation of E-cadherin and reduces the membrane-localized E-cadherin probably due to increase of its endocytosis. Fluoxetine inhibits spreading of β cells on E-cad/Fc coated slides and also disrupts E-cadherin-mediated actin filaments. Additionally, fluoxetine significantly suppresses endoplasmic reticulum (ER) calcium release and store-operated calcium entry (SOCE) activation, probably through reduction of ER calcium storage and inhibition of stromal interaction molecule 1 (STIM1) trafficking. These data suggest that exposure to fluoxetine results in impaired β cell functions, occurring in concert with reduction of E-cadherin-dependent cell adhesion and alterations of calcium homeostasis.

show abstract

Fluoxetine Impairs Insulin Secretion without Modifying Extracellular Serotonin Levels in MIN6 β-cells

Abstract: The inhibitory effect of fluoxetine on β-cell glucose stimulated insulin secretion is not mediated by blockage of 5HT transporter through SERT.

Cited by 15 publications

References 30 publications

Serotonergic regulation of insulin secretion

Serotonergic regulation of insulin secretion

Editor’s Highlight: Therapeutic Concentrations of Antidepressants Inhibit Pancreatic Beta-Cell Function via Mitochondrial Complex Inhibition

Selective serotonin reuptake inhibitor, fluoxetine, impairs E-cadherin-mediated cell adhesion and alters calcium homeostasis in pancreatic beta cells

Contact Info

Product

Resources

About