Tungstate promotes ß-cell survival in Irs2-/- mice.
Am J Physiol Endocrinol Metab
; 306(1): E36-47, 2014 Jan 01.
Article
en En
| MEDLINE
| ID: mdl-24253047
ABSTRACT
Pancreatic ß-cells play a central role in type 2 diabetes (T2D) development, which is characterized by the progressive decline of the functional ß-cell mass that is associated mainly with increased ß-cell apoptosis. Thus, understanding how to enhance survival of ß-cells is key for the management of T2D. The insulin receptor substrate-2 (IRS-2) protein is pivotal in mediating the insulin/IGF signaling pathway in ß-cells. In fact, IRS-2 is critically required for ß-cell compensation in conditions of increased insulin demand and for ß-cell survival. Tungstate is a powerful antidiabetic agent that has been shown to promote ß-cell recovery in toxin-induced diabetic rodent models. In this study, we investigated whether tungstate could prevent the onset of diabetes in a scenario of dysregulated insulin/IGF signaling and massive ß-cell death. To this end, we treated mice deficient in IRS2 (Irs2(-/-)), which exhibit severe ß-cell loss, with tungstate for 3 wk. Tungstate normalized glucose tolerance in Irs2(-/-) mice in correlation with increased ß-cell mass, increased ß-cell replication, and a striking threefold reduction in ß-cell apoptosis. Islets from treated Irs2(-/-) exhibited increased phosphorylated Erk1/2. Interestingly, tungstate repressed apoptosis-related genes in Irs2(-/-) islets in vitro, and ERK1/2 blockade abolished some of these effects. Gene expression profiling showed evidence of a broad impact of tungstate on cell death pathways in islets from Irs2(-/-) mice, consistent with reduced apoptotic rates. Our results support the finding that ß-cell death can be arrested in the absence of IRS2 and that therapies aimed at reversing ß-cell mass decline are potential strategies to prevent the progression to T2D.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Compuestos de Tungsteno
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Células Secretoras de Insulina
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Proteínas Sustrato del Receptor de Insulina
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Hipoglucemiantes
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2014
Tipo del documento:
Article