Abstract
The prevalence of type 2 diabetes (T2D) is 2-3-fold higher among people with severe mental health disorders compared to the general population. Several lines of evidence suggest a bidirectional link between diabetes and mental illness, so prevention of T2D in patients with mental illness and management of psychiatric symptoms in diabetic patients are both clinically important. There are concerns that antidepressant and antipsychotic therapies increase the risk of developing T2D. However, different medications used to control psychiatric conditions vary in side effects related to glucose dysregulation, and the direct actions of individual medications at beta cells are not fully understood. Therefore, the experiments in this thesis focused on the effects on beta cell function of the widely prescribed selective serotonin reuptake inhibitor (SSRI) antidepressants, fluoxetine, sertraline and paroxetine, and atypical antipsychotic drugs (AAPs), aripiprazole and clozapine.SSRIs block serotonin reuptake by inhibiting the serotonin reuptake transporter (SERT). SERT mRNA was detected by standard polymerase chain reaction (PCR) amplification in MIN6 beta cells, mouse islets and human islets. In addition, SERT expression was confirmed by detection of a 71kDa immunoreactive protein by Western blotting. On the other hand, AAPs act on a range of receptors, including dopamine 2 (D2) receptors, and D2 receptor expression in beta cells was confirmed by quantitative PCR and fluorescent immunohistochemistry. Trypan blue exclusion tests were used to assess viability of MIN6 beta cells and mouse islets, and they showed no impairment in viability following a 48h incubation with 0.1-1µM fluoxetine, 0.1-1µM sertraline, 0.01-0.1µM paroxetine, 0.1-1µM aripiprazole or 0.2-2µM clozapine. Trypan blue uptake was only evident in MIN6 cells or islets treated with fluoxetine, sertraline or aripiprazole at 10µM, paroxetine at 1µM and clozapine at 20µM. Acute exposure of mouse and human islets to therapeutically relevant concentrations of SSRIs increased glucose- stimulated insulin secretion (GSIS) in perifusions. In addition, exposure of MIN6 cells, mouse islets and human islets to SSRIs or AAPs for 1h or 48h in static incubation experiments significantly potentiated glucose-induced insulin secretion.
The effects of SSRIs and AAPs in regulating beta cell proliferation were investigated by quantifying bromodeoxyuridine (BrdU) incorporation into beta cell DNA. Fluoxetine, sertraline, paroxetine, and aripiprazole, but not clozapine, significantly increased MIN6 beta cell proliferation following a 48h incubation, and aripiprazole and clozapine increased proliferation of islet-derived pseudoislets. In addition, male ob/ob mice that were injected with fluoxetine (10mg/kg) 4 times over 14 days showed significant increases in islet size and the number of BrdU-positive beta cells. Moreover, quantitative Western blot analysis revealed that fluoxetine increased phosphorylation of mitogen-activated protein kinase (MAPK), cAMP response element-binding protein (CREB), and protein kinase B, also known as Akt, which are known to be involved in beta cell mass expansion.
Levels of apoptosis of beta cells are low, therefore apoptosis of MIN6 beta cells, mouse islets and human islets was induced by a saturated free fatty acid, palmitate, or a cocktail of proinflammatory cytokines (interleukin-1β, tumour necrosis factor α, and interferon γ). SSRIs and AAPs had no effect on basal apoptosis rates, but they had a protective effect against palmitate- and cytokine- induced apoptosis.
In summary, the data presented in this thesis have demonstrated that therapeutically relevant concentrations of fluoxetine, sertraline, paroxetine, as well as aripiprazole and clozapine, potentiate acute dynamic glucose-stimulated insulin secretion, with no impairment of viability, and they also promote beta cell proliferation and have a protective effect against palmitate- and cytokine- induced apoptosis. Therefore, these data indicating that these SSRIs and AAPs exert beneficial effects on beta cell mass and function suggest that glucose dysregulation observed with their use is not secondary to adverse effects at beta cells.
| Date of Award | 1 Mar 2022 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Shanta Persaud (Supervisor) & Bo Liu (Supervisor) |