Referencia

Diabetes. 2013 Jul;62(7):2308-17. doi: 10.2337/db12-1097. Epub 2013 Jan 24.

Autores

Lanuza-Masdeu Jordi, Arévalo María Isabel, Vila Cristina, Barberà Albert, Gomis Ramon, Caelles Carme.

Resumen

Insulin resistance is a key condition in the development of type 2 diabetes. It is well established that exacerbated Jun NH2-terminal kinase (JNK) activity is involved in promoting insulin resistance in peripheral insulin-target tissues; however, this involvement is less documented in pancreatic β-cells. Using a transgenic mouse model, here we show that JNK activation in β-cells led to glucose intolerance as a result of impaired capacity to increase insulinemia in response to hyperglycemia. Pancreatic islets from these mice showed no obvious morphostructural abnormalities or decreased insulin content. In contrast, these islets failed to secrete insulin in response to glucose or insulin but were competent in succinate-, ketoisocaproate-, 3-isobutyl-1-methylxanthine (IBMX-), KCl-, and tolbutamide-induced insulin secretion. At the molecular level, JNK activation in β-cells inhibited insulin-induced Akt phosphorylation, pancreatic and duodenal homeobox 1 nucleocytoplasmic shuttling, and transcription of insulin-target genes. Remarkably, rosiglitazone restored insulin secretion in response to hyperglycemia in mice and insulin-induced insulin secretion and signaling in isolated islets. In conclusion, the mere activation of JNK suffices to induce insulin resistance in pancreatic β-cells by inhibition of insulin signaling in these cells, but it is not sufficient to elicit β-cell death. In addition, we provide the first evidence that thiazolidinediones exert insulin-sensitizing action directly on pancreatic β-cells.

Descripción

La activación de la Jun NH2-terminal kinase (JNK) en tejidos periféricos conduce a la resistencia a insulina, una característica clave en el desarrollo de la diabetes tipo 2. Con la ayuda de un ratón transgénico que permite activar a JNK específicamente en las células productoras de insulina, se ha podido recapitular en estas células la resistencia a insulina, lo que conlleva intolerancia a la glucosa. Este fenotipo no implica otras alteraciones en los islotes pancreáticos y es reversible con rosiglitazona.

grupo

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de investigación sobre señalización celular quiere llegar a comprender los mecanismos de regulación y de diafonía que fundamentan la transducción de señales. Actualmente está centrado en los mecanismos de diafonía que permiten la interacción de dos receptores nucleares, Receptor de Glucocorticoides y PPAR-γ, y la vía JNK/AP-1.

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