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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Chronic use of pravastatin reduces insulin exocytosis and increases beta-cell death in hypercholesterolemic mice

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Lorza-Gil, Estela [1] ; Salerno, Alessandro G. [1] ; Wanschel, Amarylis C. B. A. [1] ; Vettorazzi, Jean F. [1] ; Ferreira, Monica S. [2] ; Rentz, Thiago [1] ; Catharino, Rodrigo R. [2] ; Oliveira, Helena C. F. [1]
Total Authors: 8
[1] Univ Estadual Campinas, Inst Biol, Dept Struct & Funct Biol, Rua Monteiro Lobato 255, BR-13083862 Campinas, SP - Brazil
[2] Univ Estadual Campinas, Fac Med Sci, Dept Clin Pathol, Rua Monteiro Lobato 255, BR-13083862 Campinas, SP - Brazil
Total Affiliations: 2
Document type: Journal article
Source: Toxicology; v. 344, p. 42-52, FEB 17 2016.
Web of Science Citations: 9

We have previously demonstrated that hypercholesterolemic LDL receptor knockout (LDLr-/-) mice secrete less insulin than wild-type mice. Removing cholesterol from isolated islets using methyl-beta-cyclodextrin reversed this defect. In this study, we hypothesized that in vivo treatment of LDLr-/- mice with the HMGCoA reductase inhibitor pravastatin would improve glucose-stimulated insulin secretion. Female LDLr-/- mice were treated with pravastatin (400 mg/L) for 1-3 months. Isolated pancreatic islets were assayed for insulin secretion rates, intracellular calcium oscillations, cholesterol levels, NAD(P)H and SNARE protein levels, apoptosis indicators and lipidomic profile. Two months pravastatin treatment reduced cholesterol levels in plasma, liver and islets by 35%, 25% and 50%, respectively. Contrary to our hypothesis, pravastatin treatment increased fasting and fed plasma levels of glucose and decreased markedly (40%) fed plasma levels of insulin. In addition, ex vivo glucose stimulated insulin secretion was significantly reduced after two and three months (36-48%, p<0.05) of pravastatin treatment. Although reducing insulin secretion and insulinemia, two months pravastatin treatment did not affect glucose tolerance because it improved global insulin sensitivity. Pravastatin induced islet dysfunction was associated with marked reductions of exocytosis-related SNARE proteins (SNAP25, Syntaxin 1A, VAMP2) and increased apoptosis markers (Bax/Bcl2 protein ratio, cleaved caspase-3 and lower NAD(P)H production rates) observed in pancreatic islets from treated mice. In addition, several oxidized phospholipids, tri- and diacylglycerols and the proapoptotic lipid molecule ceramide were identified as markers of pravastatin-treated islets. Cell death and oxidative stress (H2O2 production) were confirmed in insulin secreting INS-1E cells treated with pravastatin. These results indicate that chronic treatment with pravastatin impairs the insulin exocytosis machinery and increases beta-cell death. These findings suggest that prolonged use of statins may have a diabetogenic effect. (C) 2016 Elsevier Ireland Ltd. All rights reserved. (AU)

FAPESP's process: 11/50400-0 - Mitochondrial energy metabolism, redox state and functionality in cell death and cardiometabolic and neurodegenerative disorders
Grantee:Aníbal Eugênio Vercesi
Support type: Research Projects - Thematic Grants