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Ras-GRF1 signaling is required for normal β-cell development and glucose homeostasis

AuthorsFont de Mora, Jaime; Esteban, Luis Miguel; Burks, Deborah J.; Núñez, Alejandro; Garcés, Carmen; García-Barrado, María José; Iglesias-Osma, M. Carmen; Moratinos, Julio; Santos de Dios, Eugenio
KeywordsCell growth
Issue DateJun-2003
PublisherNature Publishing Group
CitationEMBO J. 2003 June 16; 22(12): 3039–3049
AbstractDevelopment of diabetes generally reflects an inadequate mass of insulin-producing β-cells. β-cell proliferation and differentiation are regulated by a variety of growth factors and hormones, including insulin-like growth factor I (IGF-I). GRF1 is a Ras-guanine nucleotide exchange factor known previously for its restricted expression in brain and its role in learning and memory. Here we demonstrate that GRF1 is also expressed in pancreatic islets. Interest ingly, our GRF1-deficient mice exhibit reduced body weight, hypoinsulinemia and glucose intolerance owing to a reduction of β-cells. Whereas insulin resistance is not detected in peripheral tissues, GRF1 knockout mice are leaner due to increased lipid catabolism. The reduction in circulating insulin does not reflect defective glucose sensing or insulin production but results from impaired β-cell proliferation and reduced neogenesis. IGF-I treatment of isolated islets from GRF1 knockouts fails to activate critical downstream signals such as Akt and Erk. The observed phenotype is similar to manifestations of preclinical type 2 diabetes. Thus, our observations demonstrate a novel and specific role for Ras-GRF1 pathways in the development and maintenance of normal β-cell number and function.
DescriptionFinal full-text version of the paper available at: http://www.nature.com/emboj/journal/v22/n12/index.html
Appears in Collections:(IBMCC) Artículos
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