|Title||The selective serotonin reuptake inhibitor fluoxetine improves glucose homeostasis in vivo by promoting insulin secretion and maintaining functional β-cell mass|
|Authors||Liu, B., Moulton, C.D., Ruz‐Maldonaldo, I., Zariwala, M., Ismail, K., Jones, P.M. and Persaud, S.J.|
Aim: We previously showed that therapeutically relevant concentrations of fluoxetine stimulated insulin secretion and increased beta cell proliferation in vitro. This study investigated the effect of fluoxetine on glucose homeostasis in mice and humans in vivo.
Methods: ob/ob mice were administered four doses of fluoxetine (10mg/kg body weight) or vehicle intraperitoneally over two weeks before undergoing intraperitoneal glucose tolerance tests. Bromodeoxyuridine (BrdU) (1mg/ml) was provided for seven days before they were killed. Insulin secretion from perifused islets was measured by radioimmunoassay. Islet beta cell proliferation was identified by immunohistochemistry. In a multi‐ethnic primary care cohort with newly diagnosed Type 2 diabetes, we compared patients prescribed fluoxetine with controls for one‐year changes in plasma insulin and HbA1c in univariate and multivariate analyses.
Results: Fluoxetine improved glucose handling in ob/ob mice (control vs fluoxetine; time (T) = 0: 6.7 ± 0.8 mM glucose vs 6.5 ± 0.5; p > 0.5; T = 210min: 36.3 ± 8.5 mM vs 16.5 ± 2.4; p < 0.05; n = 5), most likely a consequence of increased beta cell proliferation (BrdU positive beta cells/islet: 0.30 ± 0.17 vs 12.15 ± 2.88; n = 20; p < 0.001) and enhanced insulin secretion in response to 20mM glucose (area under the curve, pg insulin/20min: 304.8 ± 28.7 vs 464.7 ± 34.2; n = 4; p < 0.001). Patients prescribed fluoxetine (n = 14) showed significant improvement in plasma insulin vs controls (n = 615) (β = 13.35 (1.84 to 23.85), p = 0.023) after adjustment for age, gender, ethnicity vascular risk factors and change in depressive symptoms. In patients prescribed fluoxetine, HbA1c improved non‐significantly (0.54% vs 0.05%) vs controls.
Conclusions: These data support a role for fluoxetine in improving beta cell function in diabetic animals and in patients with early Type 2 diabetes. Repurposing of fluoxetine, thus, represents a novel therapeutic strategy for the management of Type 2 diabetes.
|Conference||Diabetes UK Professional Conference 2018|
|Published||14 Mar 2018|
|Journal citation||35 (S1), pp. 23-24|
|Digital Object Identifier (DOI)||doi:10.1111/dme.9_13570|