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|Type:||Artigo de periódico|
|Title:||Lower expression of PKA alpha impairs insulin secretion in islets isolated from low-density lipoprotein receptor (LDLR-/-) knockout mice|
de Oliveira, HCF
|Abstract:||Hypercholesterolemic low-density lipoprotein receptor knockout mice (LDLR-/-) show normal whole-body insulin sensitivity, but impaired glucose tolerance due to a reduced insulin secretion in response to glucose. Here, we investigate the possible mechanisms involved in such a defect in isolated LDLR-/- mice islets. Low-fat chow-fed female and male mice aged 20 weeks, LDLR-/- mice, and wild-type (WT) mice were used in this study. Static insulin secretion, cytoplasmatic Ca2+ analysis, and protein expression were measured in islets isolated from LDLR-/- and WT mice. At basal (2.8 mmol/L) and stimulatory (11.1 mmol/L) glucose concentrations, the insulin secretion rates induced by depolarizing agents such as KCl, L-arginine, and tolbutamide were significantly reduced in LDLR-/- when compared with control (WT) islets. In addition, KCl-induced Ca2+ influx at 2.8 mmol/L glucose was lower in LDLR-/- islets, suggesting a defect downstream of the substrate metabolism step of the insulin secretion pathway. Insulin secretion induced by the protein kinase A (PKA) activators forskolin and 3-isobutyl-1-methyl-xanthine, in the presence of 11.1 mmol/L glucose, was lower in LDLR-/- islets and was normalized in the presence of the protein kinase C pathway activators carbachol and phorbol 12-myristate 13-acetate. Western blotting analysis showed that phospholipase C beta(2) expression was increased and PKA alpha was decreased in LDLR-/- compared with WT islets. Results indicate that the lower insulin secretion observed in islets from LDLR-/- mice at postprandial levels of glucose can be explained, at least in part, by the reduced expression of PKA alpha in these islets. (C) 2011 Elsevier Inc. All rights reserved.|
|Editor:||W B Saunders Co-elsevier Inc|
|Appears in Collections:||Artigos e Materiais de Revistas Científicas - Unicamp|
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