Fluoxetine-induced pancreatic beta cell dysfunction: New insight into the benefits of folic acid in the treatment of depression

Abstract

Background

Major depressive disorder is a common psychiatric illness with reported prevalence rates of 12–16% in persons aged 12 and over. Depression is also associated with a high risk of new onset of type 2 diabetes (T2D). This relationship between depression and diabetes may be related to depression itself and/or drugs prescribed. Importantly, the use of selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed class of antidepressants, increases the risk of developing T2D. However, the mechanism(s) underlying this association remains elusive.

Methods

Here we examine the effects of the SSRI fluoxetine (Prozac®) on beta cell function utilizing INS-1E cells, a rat beta cell line, to elucidate the underlying molecular mechanisms.

Results

Fluoxetine treatment significantly reduced glucose stimulated insulin secretion (GSIS). This decreased beta cell function was concomitant with an increased production of reactive oxygen species and oxidative damage which may contribute to decreased mitochondrial electron transport chain enzyme (ETC) activity. Importantly the fluoxetine-induced deficits in beta cell function were prevented by the addition of the antioxidant folic acid.

Limitations

These studies were conducted in vitro; the in vivo relevance remains to be determined.

Conclusions

These findings suggest that use of SSRI antidepressants may increase the risk of new-onset T2D by causing oxidative stress in pancreatic beta cells. However, folic acid supplementation in patients taking SSRIs may reduce the risk of new onset diabetes via protection of normal beta cell function.

Introduction

Patients with major mental illnesses have an increased risk of metabolic disorders including type 2 diabetes (T2D) (Pan et al., 2012, Renn et al., 2011). Established risk factors for the increased incidence of T2D in patients with depression include: familiarity and genetic predisposition; socioeconomic status; maladaptive behaviors during a depressive episode such as comfort eating and physical inactivity and psychotropic medication׳s use (McIntyre et al., 2010, Rotella and Mannucci, 2013). Antidepressants are a first-line option for the management of moderate to severe depression, and estimates suggest that in the USA alone, 27,000,000 persons are taking antidepressants (Keller et al., 2005, Olfson and Marcus, 2009). Antidepressant use in Canada is equally astounding; in the Canadian Community Health Survey (Cycle 1.2; 2002) 5.8% of Canadians were reportedly taking antidepressants (Beck et al., 2005). There is now considerable evidence from animal experiments and clinical studies that antidepressant use constitutes a major risk factor for impaired glucose homeostasis and T2D (Bhattacharjee et al., 2013, Rotella and Mannucci, 2013). Although there are a wide variety of medications available for the treatment of depression (Boonstra et al., 2011, Canadian Network for Mood and Anxiety Treatments (CANMAT), 2009, Philip et al., 2008), selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed therapy for adults, children and adolescents (Birmaher et al., 1998, Gelenberg, 2010, Canadian Network for Mood and Anxiety Treatments (CANMAT), 2009). In humans, the use of SSRIs appears to increase the risk of developing T2D. Indeed, a retrospective cohort study identified an increased odds ratio of developing T2D in children and adolescents taking SSRIs (OR=1.37; 95% CI=1.10–1.71) (Jerrell et al., 2012). Similarly, a recent large case-control study reported that long-term use of SSRIs (i.e., greater than 24 months) in adults, was associated with an increased risk of T2D (incidence rate ratio=2.06; 95% CI=1.20–3.52) (Andersohn et al., 2009). Although the mechanisms underlying the increased risk of T2D in patients with SSRI use have not been fully explored, a recent study has reported that SSRIs can directly impact pancreatic beta cell function (Isaac et al., 2013).

Isaac et al. (2013) demonstrated that high doses of (30 μM) sertraline inhibited glucose-stimulated insulin secretion (GSIS) from pancreatic islets (i.e., impaired beta cell function) and led to increased beta cell death (Isaac et al., 2013). The mitochondria plays a central role in regulating beta cell function and survival (Supale et al., 2012); notably SSRI exposure has been shown to cause mitochondrial dysfunction in a variety of cell types (Abdel-Razaq et al., 2010, Agostinho et al., 2011, Han and Lee, 2009; C. S. Lee et al., 2010) although the effects of SSRIs on beta cell mitochondrial function have not been explored. Moreover, SSRIs have also been reported to increase the production of reactive oxygen species (ROS) (Mun et al., 2013) resulting in damage to mitochondrial as well as cytoplasmic proteins, lipids and nucleic acids (Ježek et al., 2012, Supale et al., 2012, Wallace, 2005). Collectively, oxidative stress, an imbalance between the production of ROS and the cellular antioxidant defense system, plays an essential role in the development of T2D (Drews et al., 2010). Indeed, increased ROS production may have profound effects in the endocrine pancreas because pancreatic beta cells have low levels of anti-oxidant enzymes and are therefore particularly susceptible to oxidative stress (Lenzen et al., 1996, Tiedge et al., 1997). Since SSRI exposure has been shown to increase oxidative stress in a number of cell types, it is plausible to suggest that an antioxidant therapy might ameliorate SSRI-induced beta cell deficits. One such therapy is folic acid.

Results from epidemiological studies suggest that low folate may be a risk factor for depression (Gilbody et al., 2007). As a result there has been considerable interest in the use of folic acid as a treatment for depression, alone or as an adjunct to antidepressant use (Taylor et al., 2004). Interestingly, folate deficiency increases ROS production in RINm5F pancreatic beta cells (Hsu et al., 2013) and folic acid administration reduces oxidative stress in patients with type 2 diabetes (Lazalde-Ramos et al., 2012). Taken together, these data suggest that folic acid supplementation might prevent or ameliorate SSRI-induced deficits in pancreatic beta cell function.