Lower expression of PKAα impairs insulin secretion in islets isolated from low-density lipoprotein receptor (LDLR−/−) knockout mice.

Autor: Bonfleur, Maria Lúcia, Ribeiro, Rosane Aparecida, Balbo, Sandra Lucinei, Vanzela, Emerielle Cristine, Carneiro, Everardo Magalhães, Franco de Oliveira, Helena Coutinho, Boschero, Antonio Carlos
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Zdroj: Metabolism: Clinical & Experimental; Aug2011, Vol. 60 Issue 8, p1158-1164, 7p
Abstrakt: 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 Cβ 2 expression was increased and PKAα 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 PKAα in these islets. [Copyright &y& Elsevier]
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