The selective serotonin reuptake inhibitors, sertraline and paroxetine, improve islet beta-cell mass and function in vitro.

AIMS: To investigate the effects of the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine at therapeutically relevant concentrations on beta-cell mass and function. METHODS: Viability was quantified in mouse insulinoma (MIN6) beta cells and mouse islets after 48-h exposure to sertraline (1-10 µM) or paroxetine (0.01-1 µM) using the Trypan blue exclusion test. The effects of therapeutic concentrations of these SSRIs on insulin secretion were determined by static incubation and perifusion experiments, while islet apoptosis was investigated by Caspase-Glo 3/7 assay, TUNEL staining and quantitative PCR analysis. Finally, proliferation of MIN6 and mouse islet beta cells was assessed by bromodeoxyuridine (BrdU) enzyme-linked immunosorbent assay and immunofluorescence. RESULTS: Sertraline (0.1-1 µM) and paroxetine (0.01-0.1 µM) were well tolerated by MIN6 beta cells and islets, whereas 10 µM sertraline and 1 µM paroxetine were cytotoxic. Exposure to 1 µM sertraline and 0.1 µM paroxetine significantly potentiated glucose-stimulated insulin secretion from mouse and human islets. Moreover, they showed protective effects against cytokine- and palmitate-induced apoptosis of islets, they downregulated cytokine-induced Stat1 and Traf1 mRNA expression, and they significantly increased proliferation of mouse beta cells. CONCLUSIONS: Our data demonstrate that sertraline and paroxetine act directly on beta cells to enhance glucose-stimulated insulin secretion and stimulate beta-cell mass expansion by increasing proliferation and decreasing apoptosis. These drugs are therefore likely to be appropriate for treating depression in people with type 2 diabetes.

The selective serotonin reuptake inhibitor fluoxetine has direct effects on beta cells, promoting insulin secretion and increasing beta-cell mass.

AIM: This study investigated whether therapeutically relevant concentrations of fluoxetine, which have been shown to reduce plasma glucose and glycated haemoglobin independent of changes in food intake and body weight, regulate beta-cell function and improve glucose homeostasis. METHODS: Cell viability, insulin secretion, beta-cell proliferation and apoptosis were assessed after exposure of MIN6 beta cells or isolated mouse and human islets to 0.1, 1 or 10 µmol/L fluoxetine. The effect of fluoxetine (10 mg/kg body weight) administration on glucose homeostasis and islet function was also examined in ob/ob mice. RESULTS: Exposure of MIN6 cells and mouse islets to 0.1 and 1 µmol/L fluoxetine for 72 hours did not compromise cell viability but 10 µmol/L fluoxetine significantly increased Trypan blue uptake. The dose of 1 µmol/L fluoxetine significantly increased beta-cell proliferation and protected islet cells from cytokine-induced apoptosis. In addition, 1 µmol/L fluoxetine induced rapid and reversible potentiation of glucose-stimulated insulin secretion from islets isolated from mice, and from lean and obese human donors. Finally, intraperitoneal administration of fluoxetine to ob/ob mice over 14 days improved glucose tolerance and resulted in significant increases in beta-cell proliferation and enhanced insulin secretory capacity. CONCLUSIONS: These data are consistent with a role for fluoxetine in regulating glucose homeostasis through direct effects on beta cells. Fluoxetine thus demonstrates promise as a preferential antidepressant for patients with concomitant occurrence of depression and diabetes.

Lipid-induced glucose intolerance is driven by impaired glucose kinetics and insulin metabolism in healthy individuals.

AIMS: Hypertriglyceridemia is associated with an increased risk of type 2 diabetes. We aimed to comprehensively examine the effects of hypertriglyceridemia on major glucose homeostatic mechanisms involved in diabetes progression. METHODS: In this randomized, cross-over, single-blinded study, two dual-labeled, 3-hour oral glucose tolerance tests were performed during 5-hour intravenous infusions of either 20 % Intralipid or saline in 12 healthy subjects (age 27.9 ± 2.6 years, 11 men, BMI 22.6 ± 1.4 kg/m2) to evaluate lipid-induced changes in insulin metabolism and glucose kinetics. Insulin sensitivity, ß cell secretory function, and insulin clearance were assessed by modeling glucose, insulin and C-peptide data. Intestinal glucose absorption, endogenous glucose production, and glucose clearance were assessed from glucose tracers. The effect of triglycerides on ß-cell secretory function was examined in perifusion experiments in murine pseudoislets and human pancreatic islets. RESULTS: Mild acute hypertriglyceridemia impaired oral glucose tolerance (mean glucose: +0.9 [0.3, 1.5] mmol/L, p = 0.008) and whole-body insulin sensitivity (Matsuda index: -1.67 [-0.50, -2.84], p = 0.009). Post-glucose hyperinsulinemia (mean insulin: +99 [17, 182] pmol/L, p = 0.009) resulted from reduced insulin clearance (-0.16 [-0.32, -0.01] L min-1 m-2, p = 0.04) and enhanced hyperglycemia-induced total insulin secretion (+11.9 [1.1, 22.8] nmol/m2, p = 0.02), which occurred despite a decline in model-derived ß cell glucose sensitivity (-41 [-74, -7] pmol min-1 m-2 mmol-1 L, p = 0.04). The analysis of tracer-derived glucose metabolic fluxes during lipid infusion revealed lower glucose clearance (-96 [-152, -41] mL/kgFFM, p = 0.005), increased 2-hour oral glucose absorption (+380 [42, 718] µmol/kgFFM, p = 0.04) and suppressed endogenous glucose production (-448 [-573, -123] µmol/kgFFM, p = 0.005). High-physiologic triglyceride levels increased acute basal insulin secretion in murine pseudoislets (+11 [3, 19] pg/aliquot, p = 0.02) and human pancreatic islets (+286 [59, 512] pg/islet, p = 0.02). CONCLUSION: Our findings support a critical role for hypertriglyceridemia in the pathogenesis of type 2 diabetes in otherwise healthy individuals and dissect the glucose homeostatic mechanisms involved, encompassing insulin sensitivity, ß cell function and oral glucose absorption.