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Co-administration of paroxetine and pravastatin causes deregulation of glucose homeostasis in diabetic rats via enhanced paroxetine exposure.

ABSTRACT: AIM: Clinical evidence shows that co-administration of pravastatin and paroxetine deregulates glucose homeostasis in diabetic patients. The aim of this study was to verify this phenomenon in diabetic rats and to elucidate the underlying mechanisms. METHODS: Diabetes mellitus was induced in male SD rats by a high-fat diet combined with a low-dose streptozotocin injection. The rats were orally administered paroxetine (10 mg/kg) and pravastatin (10 mg/d) or both the drugs daily for 28 d. The pharmacokinetics of paroxetine and pravastatin were examined on d 1 and d 28. Biochemical parameters including serum insulin, glucose and lipids were monitored during the treatments. An insulin-secreting cell line (INS-1) was used for measuring insulin secretion. RESULTS: In diabetic rats, co-administration of paroxetine and pravastatin markedly increased the concentrations of both the drugs compared with administration of each drug alone. Furthermore, co-administration severely impaired glucose homeostasis in diabetic rats, as demonstrated by significantly increased serum glucose level, decreased serum and pancreatic insulin levels, and decreased pancreatic Insulin-2 mRNA and tryptophan hydroxylase-1 (Tph-1) mRNA levels. Treatment of INS-1 cells with paroxetine (5 and 10 μmol/L) significantly inhibited insulin secretion, decreased the intracellular insulin, 5-HT, Insulin-2 mRNA and Tph-1 mRNA levels. Treatment of the cells with pravastatin (10 μmol/L) significantly stimulated insulin secretion, which was weakened by co-treatment with paroxetine. CONCLUSION: Paroxetine inhibits insulin secretion at least via decreasing intracellular 5-HT and insulin biosynthesis. The deregulation of glucose homeostasis by co-administration of paroxetine and pravastatin in diabetic rats can be attributed to enhanced paroxetine exposure.

SUBMITTER: Li F

PROVIDER: S-EPMC4086381 | biostudies-other | 2014 Jun

REPOSITORIES: biostudies-other

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Project description:BackgroundExposure to per- and polyfluoroalkyl substances (PFAS), a prevalent class of persistent pollutants, may increase the risk of type 2 diabetes.ObjectiveWe examined associations between PFAS exposure and glucose metabolism in youth.MethodsOverweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; n=310) participated in annual visits for an average of 3.3±2.9y. Generalizability of findings were tested in young adults from the Southern California Children's Health Study (CHS; n=135) who participated in a clinical visit with a similar protocol. At each visit, oral glucose tolerance tests were performed to estimate glucose metabolism and β-cell function via the insulinogenic index. Four PFAS were measured at baseline using liquid chromatography-high-resolution mass spectrometry; high levels were defined as concentrations >66th percentile.ResultsIn females from the SOLAR, high perfluorohexane sulfonate (PFHxS) levels (≥2.0 ng/mL) were associated with the development of dysregulated glucose metabolism beginning in late puberty. The magnitude of these associations increased postpuberty and persisted through 18 years of age. For example, postpuberty, females with high PFHxS levels had 25-mg/dL higher 60-min glucose (95% CI: 12, 39mg/dL; p<0.0001), 15-mg/dL higher 2-h glucose (95% CI: 1, 28mg/dL; p=0.04), and 25% lower β-cell function (p=0.02) compared with females with low levels. Results were largely consistent in the CHS, where females with elevated PFHxS levels had 26-mg/dL higher 60-min glucose (95% CI: 6.0, 46mg/dL; p=0.01) and 19-mg/dL higher 2-h glucose, which did not meet statistical significance (95% CI: -1, 39mg/dL; p=0.08). In males, no consistent associations between PFHxS and glucose metabolism were observed. No consistent associations were observed for other PFAS and glucose metabolism.DiscussionYouth exposure to PFHxS was associated with dysregulated glucose metabolism in females, which may be due to changes in β-cell function. These associations appeared during puberty and were most pronounced postpuberty. https://doi.org/10.1289/EHP9200.

Project description:ObjectiveWe evaluated sodium-glucose co-transporter2 (SGLT2) expression and the effect of SGLT2 inhibitor (SGLT2i) therapies on carotid plaques of asymptomatic diabetic and non-diabetic patients.MethodsPlaques were obtained from 296 non-diabetic patients and 227 patients with type 2 diabetes undergoing carotid endarterectomy. 97 patients with type 2 diabetes were treated with SGLT2 inhibitors for 16 ± 4 months before endarterectomy. After propensity score matching analysis, patients with type 2 diabetes were categorized without (n = 87) and with SGLT2i therapy (n = 87). To investigate SGLT2 expression levels' effects on major adverse endpoints (MACE = stroke, transient ischemic attack, myocardial infarction, and death), we evaluated MACE outcomes at a 2-year follow-up.ResultsCompared to plaques from patients without diabetes, plaques from patients with diabetes had higher SGLT2 expression, inflammation, and oxidative stress, along with lower SIRT6 expression and collagen content. Compared with plaques from patients with diabetes, SGLT2i-treated patients with type 2 diabetes presented increased SIRT6 expression and collagen content and lowered inflammation and ion and oxidative stress, thus indicating a more stable plaque phenotype. These results supported in vitro observations on human aorta endothelial cells (EC) (TeloHAEC-cells). Indeed, EC treated with high glucose (25 mM) in the presence of SGLT2i (100 nM canagliflozin) presented higher SIRT6 expression and decreased mRNA and protein SGLT2 levels, nuclear factor-kappa B (NF-B(NF-κB), and matrix metallopeptidase 9 (MMP-9) expression compared to cells treated only with high glucose. After two years following endarterectomy, a multivariable Cox regression analysis showed significantly higher 2-year overall survival from MACE in patients without diabetes (P < 0.01). Among patient with diabetes, the current SGLT2i users presented a significantly lower rate of MACE through 2 years compared to non-SGLT2i users (P < 0.05).ConclusionsThese findings unveil a critical involvement of the SGLT2/SIRT6 pathway in the inflammatory process of diabetic atherosclerotic lesions and suggest its possible favorable modulation by SGLT2i.

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Co-administration of paroxetine and pravastatin causes deregulation of glucose homeostasis in diabetic rats via enhanced paroxetine exposure.

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