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|Type:||Artigo de periódico|
|Title:||Cholesterol reduction ameliorates glucose-induced calcium handling and insulin secretion in islets from low-density lipoprotein receptor, knockout mice|
de Oliveira, CA
|Abstract:||Aims/hypothesis: Changes in cellular cholesterol level may contribute to beta cell dysfunction. Islets from low density lipoprotein receptor knockout (LDLR-/-) mice have higher cholesterol content and secrete less insulin than wild-type (WT) mice. Here, we investigated the association between cholesterol content, insulin secretion and Ca2+ handling in these islets. Methods: Isolated islets from both LDLR-/- and WT mice were used for measurements of insulin secretion (radioimmunoassay), cholesterol content (fluorimetric assay), cytosolic Ca2+ level (fura-2AM) and SNARE protein expression (VAMP-2, SNAP-25 and syntaxin-1A). Cholesterol was depleted by incubating the islets with increasing concentrations (0-10 mmol/l) of methyl-beta-cyclodextrin (M beta CD). Results: The first and second phases of glucose-stimulated insulin secretion (GSIS) were lower in LDLR-/- than in WT islets, paralleled by an impairment of Ca2+ handling in the former. SNAP-25 and VAMP-2, but not syntaxin-1A, were reduced in LDLR-/- compared with WT islets. Removal of excess cholesterol from LDLR-/- islets normalized glucose- and tolbutamide-induced insulin release. Glucose-stimulated Ca2+ handling was also normalized in cholesterol-depleted LDLR-/- islets. Cholesterol removal from WT islets by 0.1 and 1.0 mmol/l M beta CD impaired both GSIS and Ca2+ handling. In addition, at 10 mmol/l M beta CD WT islet showed a loss of membrane integrity and higher DNA fragmentation. Conclusion: Abnormally high (LDLR-/- islets) or low cholesterol content (WT islets treated with M beta CD) alters both GSIS and Ca2+ handling. Normalization of cholesterol improves Ca2+ handling and insulin secretion in LDLR-/- islets. (C) 2013 Elsevier B.V. All rights reserved.|
|Editor:||Elsevier Science Bv|
|Appears in Collections:||Artigos e Materiais de Revistas Científicas - Unicamp|
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