Abstract
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.
Highlights
Patients with major depressive disorder (MDD) have a higher incidence of type 2 diabetes mellitus (T2DM) when compared to the general population[1, 2]
Cell-cell adhesion plays an important role in regulating glucose stimulated insulin secretion (GSIS) from pancreatic β cells[16, 18], so we examined whether fluoxetine can affect cell morphology, and cell-cell adhesion
We found control group with adjacent cells within each colony shared common boundaries demarcated by E-cadherin, but E-cadherin was reduced at area of cell contact and cell dispersed after fluoxetine treatment (Fig. 1B)
Summary
Patients with major depressive disorder (MDD) have a higher incidence of type 2 diabetes mellitus (T2DM) when compared to the general population[1, 2]. A recently population-based, nested case-control study in Taiwan showed a 20% increased risk of diabetes for patients with long-term antidepressant treatment for two or more years[6]. Despite these findings, little is known about the direct pathophysiology of SSRIs on pancreatic β cell functions. Modulation of cytosolic free calcium concentration ([Ca2+]i) is an important for signal transduction involved in fundamental cellular functions, such as proliferation, migration, gene regulation, and apoptosis in various cell types[20, 21] These changes either reflect alterations in calcium (Ca2+) fluxes or result from mobilization of intracellular Ca2+ stores[20, 22]. Sabourin et al demonstrated that Orai[1] and TRPC1, which form the SOCs regulated by STIM1, are implicated in insulin secretion in β cells[31]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
